EP2259807A1 - Compositions and methods for distraction osteogenesis - Google Patents
Compositions and methods for distraction osteogenesisInfo
- Publication number
- EP2259807A1 EP2259807A1 EP09708984A EP09708984A EP2259807A1 EP 2259807 A1 EP2259807 A1 EP 2259807A1 EP 09708984 A EP09708984 A EP 09708984A EP 09708984 A EP09708984 A EP 09708984A EP 2259807 A1 EP2259807 A1 EP 2259807A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pdgf
- bone
- biocompatible matrix
- composition
- distraction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 149
- 238000000034 method Methods 0.000 title claims abstract description 113
- 230000011164 ossification Effects 0.000 title claims abstract description 49
- 239000011159 matrix material Substances 0.000 claims abstract description 180
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 169
- 230000004936 stimulating effect Effects 0.000 claims abstract description 24
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 165
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 165
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 97
- 229920001436 collagen Polymers 0.000 claims description 71
- 102000008186 Collagen Human genes 0.000 claims description 70
- 108010035532 Collagen Proteins 0.000 claims description 70
- 239000002245 particle Substances 0.000 claims description 58
- 239000001506 calcium phosphate Substances 0.000 claims description 30
- 235000011010 calcium phosphates Nutrition 0.000 claims description 29
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 26
- 238000007596 consolidation process Methods 0.000 claims description 24
- 239000011148 porous material Substances 0.000 claims description 19
- 239000000872 buffer Substances 0.000 claims description 15
- 230000012292 cell migration Effects 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000000638 solvent extraction Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 description 99
- 239000000463 material Substances 0.000 description 78
- 239000011230 binding agent Substances 0.000 description 60
- -1 sodium acetate) Chemical compound 0.000 description 32
- 239000012071 phase Substances 0.000 description 25
- 238000002513 implantation Methods 0.000 description 21
- 239000002872 contrast media Substances 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 15
- 210000001519 tissue Anatomy 0.000 description 14
- 230000009969 flowable effect Effects 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108010081589 Becaplermin Proteins 0.000 description 11
- 239000012634 fragment Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 239000013543 active substance Substances 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 241000283690 Bos taurus Species 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 229920001661 Chitosan Polymers 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 230000035876 healing Effects 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 206010017076 Fracture Diseases 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 210000002805 bone matrix Anatomy 0.000 description 5
- 239000007943 implant Substances 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 108010017843 platelet-derived growth factor A Proteins 0.000 description 5
- 108010000685 platelet-derived growth factor AB Proteins 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- 239000007974 sodium acetate buffer Substances 0.000 description 5
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 4
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 4
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 4
- 102000013275 Somatomedins Human genes 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- 239000013060 biological fluid Substances 0.000 description 4
- 229940112869 bone morphogenetic protein Drugs 0.000 description 4
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 239000004023 fresh frozen plasma Substances 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 238000010603 microCT Methods 0.000 description 4
- 108010017992 platelet-derived growth factor C Proteins 0.000 description 4
- 210000004623 platelet-rich plasma Anatomy 0.000 description 4
- 235000019731 tricalcium phosphate Nutrition 0.000 description 4
- 210000000689 upper leg Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 102000012422 Collagen Type I Human genes 0.000 description 3
- 108010022452 Collagen Type I Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010020649 Hyperkeratosis Diseases 0.000 description 3
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000306 component Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000833 heterodimer Substances 0.000 description 3
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 3
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 230000001009 osteoporotic effect Effects 0.000 description 3
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 3
- 229920001432 poly(L-lactide) Polymers 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 150000004804 polysaccharides Chemical class 0.000 description 3
- 210000001236 prokaryotic cell Anatomy 0.000 description 3
- 230000008733 trauma Effects 0.000 description 3
- DVLFYONBTKHTER-UHFFFAOYSA-N 3-(N-morpholino)propanesulfonic acid Chemical compound OS(=O)(=O)CCCN1CCOCC1 DVLFYONBTKHTER-UHFFFAOYSA-N 0.000 description 2
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- 206010053555 Arthritis bacterial Diseases 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 102000055006 Calcitonin Human genes 0.000 description 2
- 108060001064 Calcitonin Proteins 0.000 description 2
- 206010008723 Chondrodystrophy Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000018386 EGF Family of Proteins Human genes 0.000 description 2
- 108010066486 EGF Family of Proteins Proteins 0.000 description 2
- 208000016264 Femoral agenesis/hypoplasia Diseases 0.000 description 2
- 208000028688 Fibular hemimelia Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 208000010300 Genu Varum Diseases 0.000 description 2
- 201000003200 Goldenhar Syndrome Diseases 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 208000004575 Infectious Arthritis Diseases 0.000 description 2
- 206010062061 Knee deformity Diseases 0.000 description 2
- 206010027541 Microgenia Diseases 0.000 description 2
- 208000009905 Neurofibromatoses Diseases 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 206010031252 Osteomyelitis Diseases 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 208000000474 Poliomyelitis Diseases 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 208000005688 Salter-Harris Fractures Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- 208000008919 achondroplasia Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001195 anabolic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003160 anti-catabolic effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 230000008468 bone growth Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 229960004015 calcitonin Drugs 0.000 description 2
- ZBZJARSYCHAEND-UHFFFAOYSA-L calcium;dihydrogen phosphate;hydrate Chemical compound O.[Ca+2].OP(O)([O-])=O.OP(O)([O-])=O ZBZJARSYCHAEND-UHFFFAOYSA-L 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000001925 catabolic effect Effects 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium phosphate dihydrate Substances O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 208000017918 hemifacial microsomia Diseases 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000032631 intramembranous ossification Effects 0.000 description 2
- 229960004647 iopamidol Drugs 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 201000004931 neurofibromatosis Diseases 0.000 description 2
- 229910000392 octacalcium phosphate Inorganic materials 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 210000002997 osteoclast Anatomy 0.000 description 2
- 230000002188 osteogenic effect Effects 0.000 description 2
- 230000002138 osteoinductive effect Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 238000010647 peptide synthesis reaction Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 229920006209 poly(L-lactide-co-D,L-lactide) Polymers 0.000 description 2
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 238000009877 rendering Methods 0.000 description 2
- 201000001223 septic arthritis Diseases 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- YIGWVOWKHUSYER-UHFFFAOYSA-F tetracalcium;hydrogen phosphate;diphosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O YIGWVOWKHUSYER-UHFFFAOYSA-F 0.000 description 2
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 description 2
- 239000003634 thrombocyte concentrate Substances 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- QHQZEEGNGSZBOL-UHFFFAOYSA-N 2-(aminomethyl)-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(CO)(CO)CO QHQZEEGNGSZBOL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- RFRMMZAKBNXNHE-UHFFFAOYSA-N 6-[4,6-dihydroxy-5-(2-hydroxyethoxy)-2-(hydroxymethyl)oxan-3-yl]oxy-2-(hydroxymethyl)-5-(2-hydroxypropoxy)oxane-3,4-diol Chemical compound CC(O)COC1C(O)C(O)C(CO)OC1OC1C(O)C(OCCO)C(O)OC1CO RFRMMZAKBNXNHE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241001631457 Cannula Species 0.000 description 1
- 229920000049 Carbon (fiber) Polymers 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 102000000503 Collagen Type II Human genes 0.000 description 1
- 108010041390 Collagen Type II Proteins 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000016942 Elastin Human genes 0.000 description 1
- 108010014258 Elastin Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 description 1
- 108010027258 GEM 21S Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 235000003332 Ilex aquifolium Nutrition 0.000 description 1
- 241000209027 Ilex aquifolium Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 241000906034 Orthops Species 0.000 description 1
- 229940121682 Osteoclast inhibitor Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002518 Polyallylamine hydrochloride Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 102000019307 Sclerostin Human genes 0.000 description 1
- 108050006698 Sclerostin Proteins 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- 108050003627 Wnt Proteins 0.000 description 1
- 102000006757 Wnt Receptors Human genes 0.000 description 1
- 108010047118 Wnt Receptors Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000011449 brick Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 description 1
- JUNWLZAGQLJVLR-UHFFFAOYSA-J calcium diphosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 description 1
- ROPDWRCJTIRLTR-UHFFFAOYSA-L calcium metaphosphate Chemical compound [Ca+2].[O-]P(=O)=O.[O-]P(=O)=O ROPDWRCJTIRLTR-UHFFFAOYSA-L 0.000 description 1
- 229940043256 calcium pyrophosphate Drugs 0.000 description 1
- 229940069978 calcium supplement Drugs 0.000 description 1
- 239000004917 carbon fiber Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 229960000633 dextran sulfate Drugs 0.000 description 1
- 235000019821 dicalcium diphosphate Nutrition 0.000 description 1
- OLSDWRNWUGHKSY-UHFFFAOYSA-J dicalcium;phosphonato phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O OLSDWRNWUGHKSY-UHFFFAOYSA-J 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 210000002082 fibula Anatomy 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000002962 histologic effect Effects 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- QZUPTXGVPYNUIT-UHFFFAOYSA-N isophthalamide Chemical compound NC(=O)C1=CC=CC(C(N)=O)=C1 QZUPTXGVPYNUIT-UHFFFAOYSA-N 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229910000150 monocalcium phosphate Inorganic materials 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000004820 osteoconduction Effects 0.000 description 1
- 230000004819 osteoinduction Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920001983 poloxamer Chemical class 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920000371 poly(diallyldimethylammonium chloride) polymer Polymers 0.000 description 1
- 229920001042 poly(δ-valerolactone) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001299 polypropylene fumarate Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009145 protein modification Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 229940116157 regranex Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229960002901 sodium glycerophosphate Drugs 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- REULQIKBNNDNDX-UHFFFAOYSA-M sodium;2,3-dihydroxypropyl hydrogen phosphate Chemical compound [Na+].OCC(O)COP(O)([O-])=O REULQIKBNNDNDX-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003232 water-soluble binding agent Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1858—Platelet-derived growth factor [PDGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to compositions and methods for use in osteodistraction procedures.
- Osteodistraction or distraction osteogenesis is the process by which the slow, incremental distraction of fracture callus is used to stimulate and prolong active bone formation, thereby providing a means of bridging what would otherwise be a large bony defect.
- Distraction osteogenesis is used in the reconstruction of skeletal deformities and the lengthening of bones, such as in the treatment of pediatric limb length inequality.
- the bone is surgically split in two segments, and the two ends of the bone are gradually moved apart (distraction phase).
- the rate at which the two bone segments are moved apart is slow enough so that new bone can form in the gap.
- a consolidation phase follows.
- Stage I The intervening gap initially is composed of fibrous tissue (longitudinally oriented collagen with spindle-shaped fibroblasts within a mesenchymal matrix of undifferentiated cells).
- Stage II Slender trabeculae of bone are observed extending from the bony edges. Early bone formation advances along collagen fibers with osteoblasts on the surface of these early bony spicules laying down bone matrix. Histochemically, significantly increased levels of alkaline phosphatase, pyruvic acid, and lactic acid are noted.
- Stage III Remodeling begins with advancing zones of bone apposition and resorption and an increase in the number of osteoclasts.
- Stage IV Early compact cortical bone is formed adjacent to the mature bone of the sectioned bone ends, with increasingly less longitudinally oriented bony spicules; this resembles the normal architecture.
- Bone remodeling begins during the consolidation phase and continues over 1-2 years, eventually transforming the regenerated bone into a mature osseous structure similar in size and shape to the adjacent bone. Although the volume of new bone is comparable to that of adjacent bones, animal studies show that mineral content and radiodensity is approximately 30% less, as is the tensile strength of the regenerated segment.
- delayed consolidation following distraction is a troubling complication.
- removal of bone fixators is postponed and the risk of other complications, such as infection, is increased.
- the present invention provides compositions and methods for stimulating osteogenesis during and/or following bone distraction.
- the present compositions facilitate and, in some embodiments, accelerate the bone consolidation phase following bone distraction.
- a composition of the present invention for stimulating osteogenesis during and/or following bone distraction comprises a solution comprising platelet derived growth factor (PDGF) and a biocompatible matrix, wherein the solution is disposed in the biocompatible matrix.
- PDGF platelet derived growth factor
- the concentration of PDGF within the solution may be within any of the concentration ranges stated above.
- PDGF comprises PDGF homodimers and heterodimers, including PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, PDGF-DD, and mixtures and derivatives thereof.
- PDGF comprises PDGF-BB.
- PDGF comprises a recombinant human (rh) PDGF such as recombinant human PDGF-BB (rhPDGF-BB).
- PDGF comprises PDGF fragments.
- rhPDGF-B comprises the following fragments: amino acid sequences 1-31, 1-32, 33-108, 33-109, and/or 1-108 of the entire B chain.
- the complete amino acid sequence (1- 109) of the B chain of PDGF is provided in Figure 15 of U.S. Patent No. 5,516,896.
- the rhPDGF compositions of the present invention may comprise a combination of intact rhPDGF-B (1-109) and fragments thereof. Other fragments of PDGF may be employed such as those disclosed in U.S. Patent No. 5,516,896.
- the rhPDGF-BB comprises at least 50% of intact rhPDGF-B (1-109).
- a biocompatible matrix comprises a bone scaffolding material.
- a bone scaffolding material comprises calcium phosphate.
- Calcium phosphate in some embodiments, comprises ⁇ - tricalcium phosphate.
- a bone scaffolding material comprises collagen or other biocompatible polymeric materials.
- the present invention provides a composition for stimulating osteogenesis during and/or following bone distraction comprising a PDGF solution disposed in a biocompatible matrix, wherein the biocompatible matrix comprises a bone scaffolding material and a biocompatible binder.
- the PDGF solution may have a concentration of PDGF as described above.
- a bone scaffolding material in some embodiments, comprises a calcium phosphate.
- a calcium phosphate comprises a ⁇ -tricalcium phosphate.
- a biocompatible binder comprises a material operable to promote adhesion between combined substances.
- a biocompatible binder for example, can promote adhesion between particles of a scaffolding material in the formation of a biocompatible matrix.
- a biocompatible binder comprising collagen can promote adhesion between ⁇ -TCP particles of a scaffolding material.
- biocompatible matrices include calcium phosphate particles with or without biocompatible binders or bone allograft such as demineralized freeze-dried bone allograft (DFDBA), mineralized freeze-dried bone allograft (FDBA), or particulate demineralized bone matrix (DBM).
- biocompatible matrices comprise bone allograft such as DFDBA, DBM, or other bone allograft materials including cortical bone shapes, such as blocks, wedges, cylinders, or particles, or cancellous bone particles of various shapes and sizes.
- a biocompatible binder comprises proteins, polysaccharides, nucleic acids, carbohydrates, synthetic polymers, or mixtures thereof.
- a biocompatible binder comprises collagen.
- a biocompatible binder comprises collagen, such as bovine collagen or human collagen.
- compositions for stimulating osteogenesis during and/or following bone distraction further comprise at least one contrast agent.
- Contrast agents are substances operable to at least partially provide differentiation of two or more bodily tissues when imaged and can assist in placement of compositions described herein in sites of distraction.
- Contrast agents according to some embodiments, comprise cationic contrast agents, anionic contrast agents, nonionic contrast agents, or mixtures thereof.
- contrast agents comprise radiopaque contrast agents.
- Radiopaque contrast agents comprise iodo-compounds including (S)-N,N'-bis[2-hydroxy-l-(hydroxymethyl)-ethyl]-2,4,6- triiodo-5-lactamido isophthalamide (Iopamidol) and derivatives thereof.
- compositions of the invention may be for use in treating a bone during an osteodistraction procedure and/or for use in the manufacture of a medicament useful in treating a bone during an osteodistraction procedure. It is to be understood that the use of the composition may involve any of the compositions and/or methods as described herein.
- a composition comprising a PDGF solution and a biocompatible matrix, wherein the solution is disposed in the biocompatible matrix, in the preparation of a medicament useful for stimulating osteogenesis in an osteodistraction procedure.
- a composition comprising a PDGF solution and a biocompatible matrix, wherein the solution is disposed in the biocompatible matrix, in the preparation of a medicament useful for accelerating bone consolidation in an osteodistraction procedure.
- the present invention provides a kit comprising a biocompatible matrix in a first package and a solution comprising PDGF in a second package.
- the solution comprises a predetermined concentration of PDGF.
- concentration of PDGF can be predetermined according to the nature of the osteodistraction procedure being performed.
- amount of biocompatible matrix provided by a kit can be dependent on the nature or classification of the osteodistraction procedure being performed.
- a syringe can facilitate disposition of the PDGF solution in the biocompatible matrix for application at a surgical site, such as a site of bone distraction.
- the present invention additionally provides methods for producing compositions for promoting osteogenesis.
- a method for producing a composition comprises providing a solution comprising PDGF, providing a biocompatible matrix, and disposing the solution in the biocompatible matrix.
- the present invention additionally provides methods of treating a bone during an osteodistraction procedure, and methods of promoting and/or accelerating osteogenesis during and/or following bone distraction.
- a method for stimulating and/or accelerating osteogenesis comprises providing a composition comprising a PDGF solution disposed in a biocompatible matrix and applying an effective amount of the composition to at least one site of bone distraction.
- the composition comprising a PDGF solution disposed in a biocompatible matrix is applied during bone distraction.
- the composition may be applied to the site one or more (e.g. two, three, four, five, six, seven, eight, nine, ten or more) times during bone distraction.
- the composition is applied after bone distraction.
- the composition may be applied to the site one or more (e.g. two, three, four, five, six, seven, eight, nine, ten or more) times after bone distraction.
- an effective amount of the composition is applied during and after bone distraction.
- a method of stimulating osteogenesis comprises: applying an effective amount of a composition comprising a platelet-derived growth factor (PDGF) solution disposed in a biocompatible matrix to at least one site of bone distraction.
- the composition is applied during the distraction phase of the osteodistraction procedure.
- the composition is applied during the consolidation phase of the osteodistraction procedure.
- the composition is applied during the distraction and consolidation phases of the osteodistraction procedure.
- the method comprises accelerating bone consolidation following bone distraction.
- the composition is applied to the site at least twice.
- the biocompatible matrix comprises a porous calcium phosphate.
- the calcium phosphate comprises ⁇ -TCP.
- the calcium phosphate has interconnected pores. In some embodiments, the calcium phosphate has a porosity greater than about 40%. In some embodiments, the calcium phosphate consists of particles in a range of about 100 microns to about 5000 microns in size. In some embodiments, the calcium phosphate consists of particles in a range of about 100 microns to about 300 microns in size. In some embodiments, the biocompatible matrix is resorbable such that at least about 80% of the calcium phosphate is resorbed within about one year of being implanted. In some embodiments, the calcium phosphate is capable of absorbing an amount of the PDGF solution that is equal to at least about 25% of the weight of the calcium phosphate.
- the biocompatible matrix comprises collagen. In some embodiments, the PDGF is present in the solution at a concentration of about 0.1 mg/ml to about 1.0 mg/ml. In some embodiments, the PDGF is present in the solution at a concentration of about 0.3 mg/ml. In some embodiments, the solution comprises a buffer. In some embodiments, the biocompatible matrix has a porosity that facilitates cell migration into the composition. In some embodiments, the biocompatible matrix comprises collagen and ⁇ -TCP in a ratio of about 20:80. In some embodiments, the composition is injectable.
- a method for stimulating osteogenesis comprises accelerating bone consolidation following bone distraction, wherein accelerating comprises providing a composition comprising a PDGF solution disposed in a biocompatible matrix and applying the composition to a site of bone distraction.
- a method for accelerating bone union following bone distraction comprises providing a composition comprising a PDGF solution disposed in a biocompatible matrix and applying an effective amount of the composition to at least one site of bone distraction.
- a method of performing an osteodistraction procedure comprises (a) partitioning a bone into a first bone segment and a second bone segment, (b) moving at least one of the first and second bone segments to produce a space between the first and second bone segments, and (c) stimulating osteogenesis in the space, wherein stimulating osteogenesis comprises providing a composition comprising a PDGF solution disposed in a biocompatible matrix and at least partially applying an effective amount of the composition in the space.
- steps (b) and (c) can be repeated as many times as necessary to lengthen the bone any desired amount.
- a method of performing an osteodistraction procedure comprises: (a) partitioning a bone into a first bone segment and a second bone segment; (b) moving at least one of the first and second bone segments to form a space between the first and second bone segments; and (c) stimulating osteogenesis in the space, wherein stimulating osteogenesis comprises applying an effective amount of a composition comprising a PDGF solution disposed in a biocompatible matrix to the space.
- the method further comprises repeating steps (b) and (c) a number of times necessary to lengthen the bone a desired amount.
- the bone may be lengthened a total of at least about 1 mm, at least about 2 mm, at least about 3 mm, at least about 4 mm, at least about 5 mm, at least about 6 mm, at least about 8 mm, at least about 10 mm, at least about 12 mm, at least about 15 mm, at least about 20 mm, at least about 25 mm, at least about 30 mm, at least about 35 mm, at least about 50 mm, at least about 75 mm, at least about 100 mm, at least about 125 mm, at least about 150 mm, at least about 175 mm, at least about 200 mm.
- the first and second bone segments are separated by at least about 0.1 mm, at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm, at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm, at least about 0.8 mm, at least about 0.9 mm, at least about 1.0 mm per distraction step (e.g. during step (b) above).
- the first and second bone segments are separated by about 0.5 mm to about 1.5 mm per distraction step.
- the first and second bone segments are separated by about 0.8 mm to about 1.2 mm per distraction step.
- the first and second bone segments are separated by about 1 mm per distraction step.
- at least 1, at least 2, at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25 distraction steps may be performed.
- applying a composition comprising a PDGF solution disposed in a biocompatible matrix comprises injecting the composition in a site of bone distraction.
- injecting comprises percutaneous injection of the composition in the distraction site.
- the composition is injected into an open or surgically exposed site of bone distraction.
- applying the composition comprises disposing the composition in a site of bone distraction with a spatula or other device.
- the composition is applied to the distraction site once. In various embodiments, the composition is applied to the distraction site at least twice, at least three times, at least four times, at least five times, at least six times, at least eight times, at least ten times during the distraction and/or consolidation phases. In various embodiments, the composition may be administered to the distraction site more than once daily, daily, every other day, every third day, every fourth day, every fifth day, every six day, every week, or less than once per week during the distraction and/or consolidation phases. [0035] In some embodiments of methods of the present invention, the biocompatible matrix comprises a bone scaffolding material. In some embodiments, the biocompatible matrix comprises a bone scaffolding material and a biocompatible binder.
- a composition of the present invention is applied to at least one site of bone distraction during the distraction phase of an osteodistraction procedure. In other embodiments, a composition of the present invention is applied to at least one site of bone distraction during the consolidation phase following bone distraction. In a further embodiment, a composition of the present invention is applied to at least one site of bone distraction during the distraction and consolidation phases.
- osteodistraction procedures comprise those used in the treatment of bilateral mandibular hypoplasia, hemifacial microsomia, congenital short femur, fibular hemimelia, hemiatrophy, achondroplasia, neurofibromatosis, bow legs, growth plate fractures, bone defects, craniofacial applications, osteomyelitis, septic arthritis, and poliomyelitis.
- osteodistraction procedures comprise those used in the treatment of various traumas.
- Traumas requiring osteodistraction procedures can comprise fractures to long bones of the body including the femur, tibia, fibula, humerous, and/or radius. Traumas requiring osteodistraction procedures can also include fractures to the craniofacial bones. In some embodiments, for example, osteodistraction procedures can be used to lengthen bone in preparation for use with a prosthesis.
- kits for constructing compositions comprising PDGF disposed in a biocompatible matrix, the compositions being useful in facilitating and, in some embodiments, accelerating bone consolidation following bone distraction.
- Figure 1 illustrates volume of new bone formation in a distraction procedure as a function of composition administered and healing time according to one embodiment of the present invention.
- Figure 2 illustrates fraction of new bone formation in a distraction procedure as a function of composition administered and healing time according to one embodiment of the present invention.
- the present invention provides compositions and methods for stimulating and/or accelerating osteogenesis during and/or following bone distraction.
- the present compositions facilitate and, in some embodiments, accelerate the bone union and the bone consolidation phase following bone distraction.
- a composition comprises a solution comprising PDGF and a biocompatible matrix, wherein the solution is disposed in the biocompatible matrix.
- a composition comprises a PDGF solution disposed in a biocompatible matrix, wherein the biocompatible matrix comprises a bone scaffolding material and a biocompatible binder.
- distraction osteogenesis is distinct from treating fractures, in that the bone segments are gradually moved apart during the distraction phase, thus re-injuring the site repeatedly, and thus keeping the new tissue in early stage bone healing during the distraction phase.
- the state of the new tissue is soft, fibrous tissue callus (Phases I-III above), with some bone formation at the ends of the bones being distracted, and treatment of the distraction gap during the distraction phase of the procedure involves treating tissue during Phases I, II, and perhaps Phase III.
- compositions of the present invention comprise a solution comprising PDGF.
- PDGF plays an important role in regulating cell growth and migration.
- PDGF as with other growth factors, is operable to bind with the extracellular domains of receptor tyrosine kinases.
- the binding of PDGF to these transmembrane proteins activates the kinase activity of their catalytic domains located on the cytosolic side of the membrane.
- the kinases induce a variety of cellular processes that include cell growth and extracellular matrix production.
- a composition provided by the present invention comprises a solution comprising platelet derived growth factor (PDGF) and a biocompatible matrix, wherein the solution is disposed in the biocompatible matrix.
- PDGF platelet derived growth factor
- a biocompatible matrix wherein the solution is disposed in the biocompatible matrix.
- PDGF is present in the solution in a concentration ranging from about 0.01 mg/ml to about 10 mg/ml, from about 0.05 mg/ml to about 5 mg/ml, or from about 0.1 mg/ml to about 1.0 mg/ml.
- PDGF may be present in the solution at any concentration within these stated ranges.
- PDGF is present in the solution at any one of the following concentrations: about 0.05 mg/ml; about 0.1 mg/ml; about 0.15 mg/ml; about 0.2 mg/ml; about 0.25 mg/ml; about 0.3 mg/ml; about 0.35 mg/ml; about 0.4 mg/ml; about 0.45 mg/ml; about 0.5 mg/ml, about 0.55 mg/ml, about 0.6 mg/ml, about 0.65 mg/ml, about 0.7 mg/ml; about 0.75 mg/ml; about 0.8 mg/ml; about 0.85 mg/ml; about 0.9 mg/ml; about 0.95 mg/ml; about 1.0 mg/ml; or about 3.0 mg/ml.
- PDGF is present in the solution in a concentration ranging from about 0.2 mg/ml to about 2 mg/ml, from about 0.3 mg/ml to about 3 mg/ml, from about 0.4 mg/ml to about 4 mg/ml, from about 0.5 mg/ml to about 5 mg/ml, from about 0.25 mg/ml to about 0.5 mg/ml, or from about 0.2 mg/ml to about 0.75 mg/ml. It is to be understood that these concentrations are simply examples of particular embodiments, and that the concentration of PDGF may be within any of the concentration ranges stated above. [0048] Various amounts of PDGF may be used in the compositions of the present invention.
- Amounts of PDGF that could be used include amounts in the following ranges: about 1 ug to about 50 mg, about 10 ug to about 25 mg, about 100 ug to about 10 mg, and about 250 ug to about 5 m x g&.-
- the concentration of PDGF or other growth factors in embodiments of the present invention can be determined by using an enzyme-linked immunoassay as described in U.S. Patent Nos. 6,221,625, 5,747,273, and 5,290,708, or any other assay known in the art for determining PDGF concentration.
- the molar concentration of PDGF is determined based on the molecular weight of PDGF dimer (e.g., PDGF-BB; MW about 25 kDa).
- PDGF comprises PDGF homodimers and heterodimers, including PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, PDGF-DD, and mixtures and derivatives thereof.
- PDGF comprises PDGF-BB.
- PDGF comprises a recombinant human PDGF, such as rhPDGF-BB.
- PDGF comprises mixtures of the various homodimers and/or heterodimers.
- Embodiments of the present invention contemplate any combination of PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and/or PDGF-DD
- PDGF in some embodiments, can be obtained from natural sources.
- PDGF can be produced by recombinant DNA techniques.
- PDGF or fragments thereof may be produced using peptide synthesis techniques known to one of ordinary skill in the art, such as solid phase peptide synthesis.
- PDGF can be derived from biological fluids.
- biological fluids according to some embodiments, can comprise any treated or untreated fluid associated with living organisms includin 1 gO blood.
- Biological fluids in another embodiment, can also comprise blood components including platelet concentrate (PC), apheresed platelets, platelet-rich plasma (PRP), plasma, serum, fresh frozen plasma (FFP), and buffy coat (BC).
- Biological fluids in a further embodiment, can comprise platelets separated from plasma and resuspended in a physiological fluid.
- a DNA sequence encoding a single monomer e.g., PDGF B-chain or A-chain
- a DNA sequence encoding a single monomer e.g., PDGF B-chain or A-chain
- a PDGF heterodimer can be generated by inserting DNA sequences encoding for both monomeric units of the heterodimer into cultured prokaryotic or eukaryotic cells and allowing the translated monomeric units to be processed by the cells to produce the heterodimer (e.g. PDGF-AB).
- cGMP recombinant PDGF-BB can be obtained commercially from Novartis Corporation (Emeryville, CA).
- Research grade rhPDGF-BB can be obtained from multiple sources including R&D Systems, Inc. (Minneapolis, MN), BD Biosciences (San Jose, CA), and Chemicon, International (Temecula, CA).
- monomeric units can be produced in prokaryotic cells in a denatured form, wherein the denatured form is subsequently refolded into an active molecule.
- PDGF comprises PDGF fragments.
- rhPDGF-B comprises the following fragments: amino acid sequences 1-31, 1-32, 33-108, 33-109, and/or 1-108 of the entire B chain.
- the complete amino acid sequence (1-109) of the B chain of PDGF is provided in Figure 15 of U.S. Patent No. 5,516,896.
- the rhPDGF compositions of the present invention may comprise a combination of intact rhPDGF-B (1-109) and fragments thereof.
- Other fragments of PDGF may be employed such as those disclosed in U.S. Patent No. 5,516,896.
- the rhPDGF-BB comprises at least about 60% of intact rhPDGF-B (1-109). In another embodiment, the rhPDGF-BB comprises at least about 65%, 75%, 80%, 85%, 90%, 95% or 99% of intact rhPDGF-B (1-109).
- PDGF can be purified.
- Purified PDGF as used herein, comprises compositions having greater than about 95% by weight PDGF prior to incorporation in solutions of the present invention.
- the solution may be any pharmaceutically acceptable solution.
- the PDGF can be substantially purified.
- Substantially purified PDGF as used herein, comprises compositions having about 5% to about 95% by weight PDGF prior to incorporation into solutions of the present invention.
- substantially purified PDGF comprises compositions having about 65% to about 95% by weight PDGF prior to incorporation into solutions of the present invention.
- substantially purified PDGF comprises compositions having about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, or about 90% to about 95%, by weight PDGF, prior to incorporation into solutions of the present invention.
- Purified PDGF and substantially purified PDGF may be incorporated into scaffolds and binders.
- PDGF can be partially purified.
- Partially purified PDGF comprises compositions having PDGF in the context of platelet rich plasma (PRP), fresh frozen plasma (FFP), or any other blood product that requires collection and separation to produce PDGF.
- PRP platelet rich plasma
- FFP fresh frozen plasma
- Embodiments of the present invention contemplate that any of the PDGF isoforms provided herein, including homodimers and heterodimers, can be purified or partially purified.
- Compositions of the present invention containing PDGF mixtures may contain PDGF isoforms or PDGF fragments in partially purified proportions.
- Partially purified and purified PDGF in some embodiments, can be prepared as described in U.S. Patent Application Serial No. 11/159,533 (Publication No: 20060084602).
- solutions comprising PDGF are formed by solubilizing PDGF in one or more buffers.
- Buffers suitable for use in PDGF solutions of the present invention can comprise, but are not limited to, carbonates, phosphates (e.g. phosphate buffered saline), histidine, acetates (e.g. sodium acetate), acidic buffers such as acetic acid and HCl, and organic buffers such as lysine, Tris buffers (e.g.
- Buffers can be selected based on biocompatibility with PDGF and the buffer's ability to impede undesirable protein modification. Buffers can additionally be selected based on compatibility with host tissues. In some embodiments, sodium acetate buffer is used.
- the buffers may be employed at different molarities, for example about 0.1 mM to about 100 mM, about 1 mM to about 50 mM, about 5 mM to about 40 mM, about 10 mM to about 30 mM, or about 15 mM to about 25 mM, or any molarity within these ranges.
- an acetate buffer e.g. sodium acetate
- solutions comprising PDGF are formed by solubilizing lyophilized PDGF in water, wherein prior to solubilization the PDGF is lyophilized from an appropriate buffer.
- Solutions comprising PDGF can have a pH ranging from about 3.0 to about 8.0.
- a solution comprising PDGF has a pH ranging from about 5.0 to about 8.0, more preferably about 5.5 to about 7.0, most preferably about 5.5 to about 6.5, or any value within these ranges.
- the pH is about 6.0.
- the pH of solutions comprising PDGF in some embodiments, can be compatible with the prolonged stability and efficacy of PDGF or any other desired biologically active agent.
- PDGF is generally more stable in an acidic environment. Therefore, in accordance with one embodiment the present invention comprises an acidic storage formulation of a PDGF solution.
- the PDGF solution preferably has a pH from about 3.0 to about 7.0, and more preferably from about 4.0 to about 6.5.
- the biological activity of PDGF can be optimized in a solution having a neutral pH range. Therefore, in a further embodiment, the present invention comprises a neutral pH formulation of a PDGF solution.
- the PDGF solution preferably has a pH from about 5.0 to about 8.0, more preferably about 5.5 to about 7.0, most preferably about 5.5 to about 6.5.
- an acidic PDGF solution is reformulated to a neutral pH composition, wherein such composition is then used to promote bone growth at distraction sites in osteodistraction procedures.
- the PDGF utilized in the solutions is rhPDGF-BB.
- the pH of the PDGF containing solution may be altered to optimize the binding kinetics of PDGF to a matrix substrate or linker. If desired, as the pH of the material equilibrates to adjacent material, the bound PDGF may become labile.
- the pH of solutions comprising PDGF can be controlled by the buffers recited herein.
- Various proteins demonstrate different pH ranges in which they are stable. Protein stabilities are primarily reflected by isoelectric points and charges on the proteins. The pH range can affect the conformational structure of a protein and the susceptibility of a protein to proteolytic degradation, hydrolysis, oxidation, and other processes that can result in modification to the structure and/or biological activity of the protein.
- solutions comprising PDGF can further comprise additional components, such as other biologically active agents.
- solutions comprising PDGF can further comprise cell culture media, other stabilizing proteins such as albumin, antibacterial agents, protease inhibitors [e.g., ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis ⁇ eta-aminoethylether ⁇ N ⁇ N ⁇ N'-tetraacetic acid (EGTA), aprotinin, ⁇ - aminocaproic acid (EACA), etc.] and/or other growth factors such as fibroblast growth factors (FGFs), epidermal growth factors (EGFs), transforming growth factors (TGFs), keratinocyte growth factors (KGFs), insulin-like growth factors (IGFs), hepatocyte growth factors (HGFs), bone morphogenetic proteins (BMPs), or other PDGFs including compositions of PDGF-AA, PDGF-BB, PDGF-AB,
- EDTA ethylenediaminet
- compositions of the present invention also comprise a biocompatible matrix in which to dispose the PDGF solutions and may also comprise a biocompatible binder either with or without a biocompatible matrix.
- a biocompatible matrix comprises a scaffolding material.
- the scaffolding material provides the framework or scaffold for new tissue and/or bone growth to occur.
- a scaffolding material in some embodiments, comprises multi- directional and interconnected pores of varying diameters.
- a scaffolding material comprises a plurality of pockets and non-interconnected pores of various diameters in addition to the interconnected pores.
- a scaffolding material in some embodiments, comprises at least one calcium phosphate.
- a scaffolding material can comprise a plurality of calcium phosphates.
- Calcium phosphates suitable for use as a scaffolding material in some embodiments of the present invention, have a calcium to phosphorus atomic ratio ranging from 0.5 to 2.0.
- the biocompatible matrix comprises allograft such as demineralized freeze- dried bone allograft (DFDBA), particulate demineralized bone matrix (DBM), mineralized bone matrix, or combinations thereof.
- Non-limiting examples of calcium phosphates suitable for use as scaffolding materials comprise amorphous calcium phosphate, monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), ⁇ -tricalcium phosphate, ⁇ - tricalcium phosphate, hydroxyapatite (OHAp), poorly crystalline hydroxyapatite, tetracalcium phosphate (TTCP), heptacalcium decaphosphate, calcium metaphosphate, calcium pyrophosphate dihydrate, carbonated calcium phosphate, calcium pyrophosphate, hydroxyapatite, or derivatives thereof.
- MCPM monocalcium phosphate monohydrate
- MCPA monocalcium phosphate anhydrous
- DCPD dicalcium phosphate dihydrate
- DCPA dicalcium phosphate anhydrous
- OCP o
- a scaffolding material comprises a polymeric material.
- a polymeric scaffold in some embodiments, comprises collagen, polylactic acid, poly(L-lactide), poly(D,L-lactide), polyglycolic acid, poly(L-lactide-co-glycolide), poly(L-lactide-co-D,L- lactide), polyacrylate, polymethacrylate, polymethylmethacrylate, chitosan, or combinations or derivatives thereof.
- a scaffolding material comprises porous structure.
- Porous scaffolding materials can comprise pores having diameters ranging from about 1 ⁇ m to about 1 mm.
- a scaffolding material comprises macropores having diameters ranging from about 100 ⁇ m to about 1 mm or greater.
- a scaffolding material comprises mesopores having diameters ranging from about 10 ⁇ m to about 100 ⁇ m.
- a scaffolding material comprises micropores having diameters less than about 10 ⁇ m.
- Embodiments of the present invention contemplate scaffolding materials comprising macropores, mesopores, and micropores or any combination thereof.
- a porous scaffolding material in some embodiments, has a porosity greater than about 25% or greater than about 40%. In another embodiment, a porous scaffolding material has a porosity greater than about 50%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 80%, or greater than about 85%. In a further embodiment, a porous scaffolding material has a porosity greater than about 90%. In some embodiments, a porous scaffolding material comprises a porosity that facilitates cell migration into the scaffolding material.
- a scaffolding material comprises a plurality of particles.
- Scaffolding particles may be mm, ⁇ m, or submicron (nm) in size.
- Scaffolding particles in some embodiments, have an average diameter ranging from about 1 ⁇ m to about 5 mm. In other embodiments, particles have an average diameter ranging from about 1 mm to about 2 mm, from about 1 mm to about 3 mm, or from about 250 ⁇ m to about 750 ⁇ m.
- Scaffolding particles in another embodiment, have an average diameter ranging from about 100 ⁇ m to about 300 ⁇ m. In a further embodiment, scaffolding particles have an average diameter ranging from about 75 ⁇ m to about 300 ⁇ m.
- scaffolding particles have an average diameter less than about 25 ⁇ m, less than about 1 ⁇ m, or less than about 1 mm. In some embodiments, scaffolding particles have an average diameter ranging from about 100 ⁇ m to about 5 mm or from about 100 ⁇ m to about 3 mm. In other embodiments, scaffolding particles have an average diameter ranging from about 250 ⁇ m to about 2 mm, from about 250 ⁇ m to about 1 mm, or from about 200 ⁇ m to about 3 mm. Particles may also be in the range of about 1 nm to about 1 ⁇ m, less than about 500 nm, or less than about 250 nm.
- Scaffolding materials are moldable, extendable and/or injectable. Moldable, extendable, and/or injectable scaffolding materials can facilitate efficient placement of compositions of the present invention in and around sites of bone distraction. In some embodiments, moldable, extendable, and/or injectable scaffolding materials are applied to sites of bone distraction with a spatula or equivalent device. In some embodiments, scaffolding materials are flowable. Flowable scaffolding materials, in some embodiments, can be applied to a site of bone distraction through a syringe and needle or cannula. In some embodiments, the flowable scaffolding materials can be applied to a site of bone distraction percutaneously.
- flowable scaffolding materials can be applied to a surgically exposed site of bone distraction.
- scaffolding materials are provided as blocks or particles.
- scaffolding materials are bioresorbable.
- a scaffolding material in some embodiments, can be at least about 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, or 90% resorbed within one year subsequent to in vivo implantation.
- a scaffolding material can be resorbed at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85% or 90% within about 1, 3, 6, 9, 12, or 18 months of in vivo implantation.
- scaffolding materials are greater than 90% resorbed within about 1, 3, 6, 9, 12, or 18 months of in vivo implantation. Bioresorbability will be dependent on: (1) the nature of the matrix material (i.e., its chemical make up, physical structure and size); (2) the location within the body in which the matrix is placed; (3) the amount of matrix material that is used; (4) the metabolic state of the patient (diabetic/non-diabetic, osteoporotic, smoker, old age, steroid use, etc.); (5) the extent and/or type of injury treated; and (6) the use of other materials in addition to the matrix such as other bone anabolic, catabolic and anti-catabolic factors.
- a scaffolding material for use as a biocompatible matrix comprises ⁇ -tricalcium phosphate ( ⁇ -TCP).
- ⁇ -TCP can comprise a porous structure having multidirectional and interconnected pores of varying diameters.
- ⁇ -TCP comprises a plurality of pockets and non- interconnected pores of various diameters in addition to the interconnected pores.
- the porous structure of ⁇ -TCP in some embodiments, comprises macropores having diameters ranging from about 100 ⁇ m to about 1 mm or greater, mesopores having diameters ranging from about 10 ⁇ m to about 100 ⁇ m, and micropores having diameters less than about 10 ⁇ m.
- Macropores and mesopores of the ⁇ -TCP can facilitate tissue in-growth including osteoinduction and osteoconduction while macropores, mesopores and micropores can permit fluid communication and nutrient transport to support tissue and bone regrowth, throughout the ⁇ -TCP biocompatible matrix.
- ⁇ -TCP in some embodiments, can have a porosity greater than about 25%, or greater than about 40%. In other embodiments, ⁇ -TCP can have a porosity greater than about 50%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, or greater than about 85%. In a further embodiment, ⁇ -TCP can have a porosity greater than about 90%. In some embodiments, ⁇ -TCP can have a porosity that facilitates cell migration into the ⁇ -TCP.
- a scaffolding material comprises ⁇ -TCP particles.
- ⁇ -TCP particles in some embodiments, can individually demonstrate any of the pore diameters, pore structures, and porosities provided herein for scaffolding materials.
- ⁇ -TCP particles in some embodiments have an average diameter ranging from about 1 ⁇ m to about 5 mm. In other embodiments, ⁇ -TCP particles have an average diameter ranging from about 1 mm to about 2 mm, from about 1 mm to about 3 mm, from about 100 ⁇ m to about 5 mm, from about 100 ⁇ m to about 3 mm, from about 250 ⁇ m to about 2 mm, from about 250 ⁇ m to about 750 ⁇ m, from about 250 ⁇ m to about 1 mm, from about 250 ⁇ m to about 2 mm, or from about 200 ⁇ m to about 3 mm. In another embodiment, ⁇ -TCP particles have an average diameter ranging from about 100 ⁇ m to about 300 ⁇ m.
- ⁇ -TCP particles have an average diameter ranging from about 75 ⁇ m to about 300 ⁇ m. In some embodiments, ⁇ - TCP particles have an average diameter of less than about 25 ⁇ m, less than about 1 ⁇ m, or less than about 1 mm. In some embodiments, ⁇ -TCP particles have an average diameter ranging from about 1 nm to about 1 ⁇ m. In a further embodiment, ⁇ -TCP particles have an average diameter less than about 500 nm or less than about 250 nm.
- a biocompatible matrix comprising ⁇ -TCP particles in some embodiments, can be provided in a shape suitable for implantation (e.g., a sphere, a cylinder, or a block).
- a ⁇ -TCP scaffolding material is moldable, extrudable, and/or injectable thereby facilitating application of the matrix to sites of bone distraction.
- Flowable matrices may be applied through syringes, tubes, cannulas, or spatulas.
- a ⁇ -TCP scaffolding material is bioresorbable.
- a ⁇ -TCP scaffolding material can be at least about 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, or 85% resorbed about one year subsequent to in vivo implantation.
- a ⁇ -TCP scaffolding material can be greater than about 90% resorbed about one year subsequent to in vivo implantation.
- a biocompatible matrix comprises a scaffolding material and a biocompatible binder.
- Biocompatible binders can comprise materials operable to promote cohesion between combined substances.
- a biocompatible binder for example, can promote adhesion between particles of a scaffolding material in the formation of a biocompatible matrix.
- the same material may serve as both a scaffolding material and binder.
- polymeric materials described herein such as collagen and chitosan may serve as both a scaffolding material and a binder.
- Biocompatible binders in some embodiments, can comprise collagen, elastin, polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, poly( ⁇ -hydroxy acids), poly (lactones), poly(amino acids), poly (anhydrides), polyurethanes, poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly( ⁇ -hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), polylactic acid, poly(L-lactide) (PLLA), poly(D,L- lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co- D,L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyglycolic acid, polyhydroxybutyrate (PHB), poly( ⁇ -caprolactone), poly( ⁇ -valerolactone),
- Biocompatible binders in other embodiments, can comprise alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran (e.g., ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ - cyclodextrin, or sodium dextran sulfate), fibrin glue, lecithin, phosphatidylcholine derivatives, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose (e.g., methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose), a glucosamine, a proteoglycan, a starch (e.g., hydroxy
- a biocompatible binder is water-soluble.
- a water-soluble binder can dissolve from the biocompatible matrix shortly after its implantation, thereby introducing macroporosity into the biocompatible matrix. Macroporosity, as discussed herein, can increase the osteoconductivity of the implant material by enhancing the access and, consequently, the remodeling activity of the osteoclasts and osteoblasts at the implant site.
- a biocompatible binder can be present in a biocompatible matrix in an amount ranging from about 5 weight percent to about 50 weight percent of the matrix. In other embodiments, a biocompatible binder can be present in an amount ranging from about 10 weight percent to about 40 weight percent of the biocompatible matrix. In another embodiment, a biocompatible binder can be present in an amount ranging from about 15 weight percent to about 35 weight percent of the biocompatible matrix. In a further embodiment, a biocompatible binder can be present in an amount of about 20 weight percent of the biocompatible matrix. In another embodiment, a biocompatible binder can be present in a biocompatible matrix in an amount greater than about 50 weight percent or 60 weight percent of the matrix. In some embodiments, a biocompatible binder can be present in a biocompatible matrix in an amount up to about 99 weight percent of the matrix.
- a biocompatible matrix comprising a scaffolding material and a biocompatible binder can be flowable, moldable, and/or extendable.
- a biocompatible matrix can be in the form of a paste or putty.
- a biocompatible matrix in the form of a paste or putty in some embodiments, can comprise particles of a scaffolding material adhered to one another by a biocompatible binder.
- a biocompatible matrix in paste or putty form can be molded into the desired implant shape or can be molded to the contours of the implantation site.
- a biocompatible matrix in paste or putty form can be injected into an implantation site with a syringe or cannula.
- a biocompatible matrix in paste or putty form does not harden and retains a flowable and moldable form subsequent to implantation.
- a paste or putty can harden subsequent to implantation, thereby reducing matrix flowability and moldability.
- a biocompatible matrix comprising a scaffolding material and a biocompatible binder in some embodiments, is bioresorbable.
- a biocompatible matrix in such embodiments, can be resorbed within about one year of in vivo implantation.
- a biocompatible matrix comprising a scaffolding material and a biocompatible binder can be resorbed within about 1, 3, 6, or 9 months of in vivo implantation.
- a biocompatible matrix comprising a scaffolding material and a biocompatible binder can be resorbed within about 1, 3, or 6 years of in vivo implantation.
- Bioresorbablity will be dependent on: (1) the nature of the matrix material (i.e., its chemical make up, physical structure and size); (2) the location within the body in which the matrix is placed; (3) the amount of matrix material that is used; (4) the metabolic state of the patient (diabetic/non-diabetic, osteoporotic, smoker, old age, steroid use, etc.); (5) the extent and/or type of injury treated; and (6) the use of other materials in addition to the matrix such as other bone anabolic, catabolic and anti-catabolic factors.
- a biocompatible matrix can comprise a ⁇ -TCP scaffolding material and a biocompatible collagen binder.
- ⁇ -TCP scaffolding materials suitable for combination with a collagen binder are consistent with those provided hereinabove.
- a collagen binder in some embodiments, comprises any type of collagen, including Type I, Type II, and Type III collagens.
- a collagen binder comprises a mixture of collagens, such as a mixture of Type I and Type II collagen.
- a collagen binder is soluble under physiological conditions.
- Other types of collagen present in bone or musculoskeletal tissues may be employed. Recombinant, synthetic and naturally occurring forms of collagen may be used in the present invention.
- a biocompatible matrix can comprise a plurality of ⁇ -TCP particles adhered to one another with a collagen binder.
- ⁇ -TCP particles for combination with a collagen binder have an average diameter ranging from about 1 ⁇ m to about 5 mm.
- ⁇ -TCP particles have an average diameter ranging from about 1 mm to about 2 mm, from about 1 mm to about 3 mm, from about 100 ⁇ m to about 5 mm, from about 100 ⁇ m to about 3 mm, from about 250 ⁇ m to about 2 mm, from about 250 ⁇ m to about 750 ⁇ m, from about 250 ⁇ m to about 1 mm, from about 250 ⁇ m to about 2 mm, or from about 200 ⁇ m to about 3 mm.
- ⁇ -TCP particles have an average diameter ranging from about 100 ⁇ m to about 300 ⁇ m. In some embodiments, ⁇ -TCP particles have an average diameter ranging from about 75 ⁇ m to about 300 ⁇ m.
- ⁇ - TCP particles have an average diameter of less than about 25 ⁇ m, less than about 1 ⁇ m, or less than about 1 mm. In some embodiments, ⁇ -TCP particles have an average diameter ranging from about 1 nm to about 1 ⁇ m. In a further embodiment, ⁇ -TCP particles have an average diameter less than about 500 nm or less than about 250 nm.
- ⁇ -TCP particles in some embodiments, can be adhered to one another by the collagen binder so as to produce a biocompatible matrix having a porous structure.
- the porous structure of a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder demonstrates multidirectional and interconnected pores of varying diameters.
- a the biocompatible matrix comprises a plurality of pockets and non- interconnected pores of various diameters in addition to the interconnected pores.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can comprise pores having diameters ranging from about 1 ⁇ m to about 1 mm.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can comprise macropores having diameters ranging from about 100 ⁇ m to about 1 mm or greater, mesopores having diameters ranging from about 10 ⁇ m to 100 ⁇ m, and micropores having diameters less than about 10 ⁇ m.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can have a porosity greater than about 25%, or greater than about 40%.
- the biocompatible matrix can have a porosity greater than about 50%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, or greater than about 85%.
- the biocompatible matrix can have a porosity greater than about 90%.
- the biocompatible matrix can have a porosity that facilitates cell migration into the matrix.
- the ⁇ -TCP particles can individually demonstrate any of the pore diameters, pore structures, and porosities provided herein for a biocompatible matrix comprising the ⁇ -TCP and collagen binder.
- a biocompatible matrix comprising ⁇ -TCP particles can comprise a collagen binder in an amount ranging from about 5 weight percent to about 50 weight percent of the matrix.
- a collagen binder can be present in an amount ranging from about 10 weight percent to about 40 weight percent of the biocompatible matrix.
- a collagen binder can be present in an amount ranging from about 15 weight percent to about 35 weight percent of the biocompatible matrix.
- a collagen binder can be present in an amount of about 20 weight percent of the biocompatible matrix.
- a collagen binder is present in an amount of about 20 weight percent of the biocompatible matrix, and ⁇ -TCP is present in an amount of about 80 weight percent of the biocompatible matrix.
- the collagen is soluble bovine type I collagen.
- the ⁇ -TCP comprises granules having a diameter of about 100 to about 300 microns.
- the biocompatible matrix is composed of 20% soluble bovine type I collagen and 80% ⁇ -TCP granules (100-300 micron particle diameter range) by mass.
- the matrix is combined with a liquid formulation of 0.3 mg/ml rhPDGF-BB in 20 mM sodium acetate solution, pH 6.0, and the two components mixed to generate a paste that can be injected or spread over a bone surface.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can be flowable, moldable, and/or extendable.
- the biocompatible matrix can be in the form of a paste or putty.
- a paste or putty can be molded into the desired implant shape or can be molded to the contours of the implantation site.
- a biocompatible matrix in paste or putty form comprising ⁇ -TCP particles and a collagen binder can be injected into an implantation site with a syringe or cannula.
- the biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can be injected into an implantation site through e.g. a 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 gauge needle.
- a biocompatible matrix in paste or putty form comprising ⁇ - TCP particles and a collagen binder can retain a flowable and moldable form when implanted.
- the paste or putty can harden subsequent to implantation, thereby reducing matrix flowability and moldability.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder in some embodiments, can be provided in a predetermined shape such as a block, sphere, or cylinder.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can be resorbable.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can be at least about 75% resorbed about one year subsequent to in vivo implantation.
- a biocompatible matrix comprising ⁇ -TCP particles and a collagen binder can be greater than about 90% resorbed about one year subsequent to in vivo implantation.
- a solution comprising PDGF can be disposed in a biocompatible matrix to produce a composition for use in osteodistraction procedures.
- the present invention provides methods for producing compositions for stimulating osteogenesis during and/or following bone distraction.
- a method for producing such compositions comprises providing a solution comprising PDGF, providing a biocompatible matrix, and disposing the solution in the biocompatible matrix.
- PDGF solutions and biocompatible matrices suitable for combination are consistent with those described hereinabove.
- a PDGF solution can be disposed in a biocompatible matrix by soaking the biocompatible matrix in the PDGF solution.
- a PDGF solution in another embodiment, can be disposed in a biocompatible matrix by injecting the biocompatible matrix with the PDGF solution.
- injecting a PDGF solution can comprise disposing the PDGF solution in a syringe and expelling the PDGF solution into the biocompatible matrix to saturate the biocompatible matrix.
- the PDGF is absorbed into the pores of the biocompatible matrix. In some embodiments, the PDGF is adsorbed onto one or more surfaces of the biocompatible matrix, including surfaces within pores of the biocompatible matrix.
- the biocompatible matrix is capable of absorbing an amount of liquid comprising PDGF that is equal to at least about 25% of the weight of the biocompatible matrix. In various embodiments, the biocompatible matrix is capable of absorbing an amount of liquid comprising PDGF that is equal to at least about 50%, at least about 200%, at least about 300% of the weight of the biocompatible matrix.
- the biocompatible matrix can be in a predetermined shape, such as a brick or cylinder, prior to receiving a PDGF solution. Subsequent to receiving a PDGF solution, the biocompatible matrix can have a paste or putty form that is flowable, extendable, and/or injectable. In other embodiments, the biocompatible matrix can demonstrate a flowable, extendable, and/or injectable paste or putty form prior to receiving a solution comprising PDGF.
- compositions Further Comprising Biologically Active Agents
- compositions of the present invention can further comprise one or more biologically active agents in addition to PDGF.
- biologically active agents that can be incorporated into compositions of the present invention, in addition to PDGF can comprise organic molecules, inorganic materials, proteins, peptides, nucleic acids (e.g., genes, gene fragments, small-interfering ribonucleic acids [si-RNAs] gene regulatory sequences, nuclear transcriptional factors, and antisense molecules), nucleoproteins, polysaccharides (e.g., heparin), glycoproteins, and lipoproteins.
- nucleic acids e.g., genes, gene fragments, small-interfering ribonucleic acids [si-RNAs] gene regulatory sequences, nuclear transcriptional factors, and antisense molecules
- nucleoproteins e.g., genes, gene fragments, small-interfering ribonucleic acids [si-RNAs] gene regulatory sequences, nuclear transcriptional factors, and antisense molecules
- Non-limiting examples of biologically active compounds that can be incorporated into compositions of the present invention including, e.g., anti-cancer agents, antibiotics, analgesics, anti-inflammatory agents, immunosuppressants, enzyme inhibitors, antihistamines, hormones, muscle relaxants, prostaglandins, trophic factors, osteoinductive proteins, growth factors, and vaccines, are disclosed in U.S. Patent Application Serial No. 11/159,533 (Publication No: 20060084602).
- Biologically active compounds that can be incorporated into compositions of the present invention include osteostimulatory factors such as insulin-like growth factors, fibroblast growth factors, or other PDGFs.
- biologically active compounds that can be incorporated into compositions of the present invention preferably include osteoinductive and osteostimulatory factors such as bone morphogenetic proteins (BMPs), BMP mimetics, calcitonin, or calcitonin mimetics, statins, statin derivatives, fibroblast growth factors, insulin-like growth factors, growth-differentiating factors, small molecule or antibody blockers of Wnt antagonists (e.g. sclerostin, DKK, soluble Wnt receptors), and parathyroid hormone.
- BMPs bone morphogenetic proteins
- BMP mimetics such as bone morphogenetic proteins (BMPs), BMP mimetics, calcitonin, or calcitonin mimetics
- statins such as bone morphogenetic proteins (BMPs), BMP mimetics, calcitonin, or calcitonin mimetics
- statins such as bone morphogenetic proteins (BMPs), BMP mimetics, calcitonin,
- factors also include protease inhibitors, as well as osteoporotic treatments that decrease bone resorption including bisphosphonates, teriparadide, and antibodies to the activator receptor of the NF-kB (RANK) ligand.
- protease inhibitors as well as osteoporotic treatments that decrease bone resorption including bisphosphonates, teriparadide, and antibodies to the activator receptor of the NF-kB (RANK) ligand.
- Additional biologically active agents can be introduced into compositions of the present invention in amounts that allow delivery of an appropriate dosage of the agent to the implant site. In most cases, dosages are determined using guidelines known to practitioners and applicable to the particular agent in question.
- the amount of an additional biologically active agent to be included in a composition of the present invention can depend on such variables as the type and extent of the condition, the overall health status of the particular patient, the formulation of the biologically active agent, release kinetics, and the bioresorbability of the biocompatible matrix. Standard clinical trials may be used to optimize the dose and dosing frequency for any particular additional biologically active agent.
- a composition of the present invention can further comprise the addition of additional grafting materials with PDGF including autologous bone marrow, autologous platelet extracts, allografts, synthetic bone matrix materials, xenografts, and derivatives thereof.
- additional grafting materials with PDGF including autologous bone marrow, autologous platelet extracts, allografts, synthetic bone matrix materials, xenografts, and derivatives thereof.
- compositions for stimulating osteogenesis during and/or following bone distraction further comprise at least one contrast agent.
- Contrast agents are substances operable to at least partially provide differentiation of two or more bodily tissues when imaged. Contrast agents, according to some embodiments, comprise cationic contrast agents, anionic contrast agents, nonionic contrast agents, or mixtures thereof. In some embodiments, contrast agents comprise radiopaque contrast agents.
- Radiopaque contrast agents comprise iodo-compounds including (S)-N,N'-bis[2-hydroxy-l-(hydroxymethyl)-ethyl]-2,4,6- triiodo-5-lactamidoisophthalamide (Iopamidol) and derivatives thereof.
- a method for stimulating and/or accelerating osteogenesis comprises providing a composition comprising a PDGF solution disposed in a biocompatible matrix and applying an effective amount of the composition to at least one site of bone distraction.
- the composition comprising a PDGF solution disposed in a biocompatible matrix is applied during bone distraction.
- the composition is applied after bone distraction.
- an effective amount of the composition is applied during and after bone distraction.
- a method for accelerating bone union following bone distraction comprises providing a composition comprising a PDGF solution disposed in a biocompatible matrix and applying an effective amount of the composition to at least one site of bone distraction.
- a method of performing an osteodistraction procedure comprises (a) partitioning a bone into a first bone segment and a second bone segment, (b) moving at least one of the first and second bone segments to produce a space between the first and second bone segments, and (c) stimulating osteogenesis in the space, wherein stimulating osteogenesis comprises providing a composition comprising a PDGF solution disposed in a biocompatible matrix and at least partially disposing an effective amount of the composition in the space.
- steps (b) and (c) can be repeated as many times as necessary to lengthen the bone any desired amount.
- applying the composition comprises injecting the composition in a site of bone distraction.
- injecting comprises percutaneous injection of the composition in the distraction site.
- the composition is injected into an open or surgically exposed site of bone distraction.
- applying the composition comprises disposing (e.g. spreading) the composition in a site of bone distraction with a spatula or other device.
- the composition can be injected into the implantation site through e.g. a 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 gauge needle.
- the biocompatible matrix comprising a bone scaffolding material.
- the biocompatible matrix comprises a bone scaffolding material and a biocompatible binder.
- a composition of the present invention is applied to at least one site of bone distraction during the distraction phase of an osteodistraction procedure. In other embodiments, a composition of the present invention is applied to at least one site of bone distraction during the consolidation phase following bone distraction. In a further embodiment, a composition of the present invention is applied to at least one site of bone distraction during the distraction and consolidation phases.
- the bone may be lengthened a total of at least about 1 mm, at least about 2 mm, at least about 3 mm, at least about 4 mm, at least about 5 mm, at least about 6 mm, at least about 8 mm, at least about 10 mm, at least about 12 mm, at least about 15 mm, at least about 20 mm, at least about 25 mm, at least about 30 mm, at least about 35 mm, at least about 50 mm, at least about 75 mm, at least about 100 mm, at least about 125 mm, at least about 150 mm, at least about 175 mm, at least about 200 mm.
- the first and second bone segments are separated by at least about 0.1 mm, at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm, at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm, at least about 0.8 mm, at least about 0.9 mm, at least about 1.0 mm per distraction step (e.g. during step (b) above).
- the first and second bone segments are separated by about 0.5 mm to about 1.5 mm per distraction step.
- the first and second bone segments are separated by about 0.8 mm to about 1.2 mm per distraction step.
- the first and second bone segments are separated by about 1 mm per distraction step.
- the composition is applied to the distraction site once.
- the composition is applied to the distraction site at least twice, at least three times, at least four times, at least five times, at least six times, at least eight times, at least ten times during the distraction and/or consolidation phases.
- the composition may be administered to the distraction site more than once daily, daily, every other day, every third day, every fourth day, every fifth day, every six day, every week, or less than once per week during the distraction and/or consolidation phases.
- mm 3 bone volume
- BV/TV bone volume fraction
- mm 3 bone volume
- BV/TV bone volume fraction
- osteodistraction procedures comprise those used in the treatment of bilateral mandibular hypoplasia, hemifacial microsomia, congenital short femur, fibular hemimelia, hemiatrophy, achondroplasia, neurofibromatosis, bow legs, growth plate fractures, bone defects, craniofacial applications, osteomyelitis, septic arthritis, and poliomyelitis.
- a methods of the present invention further comprise providing at least one pharmaceutical composition in addition to the composition comprising a PDGF solution disposed in a biocompatible matrix and administering the at least one pharmaceutical composition locally and/or systemically.
- the at least one pharmaceutical composition in some embodiments, comprises vitamins, such as vitamin D 3 , calcium supplements, or any osteoclast inhibitor known to one of skill in the art, including bisphosphonates.
- the at least one pharmaceutical composition is administered locally.
- the at least one pharmaceutical composition can be incorporated into the biocompatible matrix or otherwise disposed in and around a site of bone distraction.
- the at least one pharmaceutical composition is administered systemically to a patient.
- the at least one pharmaceutical composition is administered orally to a patient.
- the at least one pharmaceutical composition is administered intravenously to a patient.
- composition comprising a solution of PDGF and a biocompatible matrix was prepared according to the following procedure.
- a pre-weighed block of biocompatible matrix comprising ⁇ -TCP and collagen was obtained.
- the ⁇ -TCP comprised ⁇ -TCP particles having an average size ranging from about 100 ⁇ m to about 300 ⁇ m.
- the ⁇ -TCP particles were formulated with about 20 weight percent soluble Type I bovine collagen binder.
- Such a ⁇ -TCP/collagen biocompatible matrix can be commercially obtained from Kensey Nash (Exton, Pennsylvania).
- rhPDGF-BB is commercially available from Novartis Corporation at a stock concentration of 10 mg/ml (i.e., Lot # QA2217) in a sodium acetate buffer.
- the rhPDGF-BB is produced in a yeast expression system by Novartis Corporation and is derived from the same production facility as the rhPDGF-BB that is utilized in the products REGRANEX, (Johnson &Johnson) and GEM 21S (BioMimetic Therapeutics) which has been approved for human use by the United States Food and Drug Administration.
- This rhPDGF-BB is also approved for human use in the European Union and Canada.
- the rhPDGF-BB solution was diluted to 0.3 mg/ml in the sodium acetate buffer.
- the rhPDGF-BB solution can be diluted to any desired concentration according to embodiments of the present invention.
- a ratio of about 3 ml of rhPDGF-BB solution to about 1 g dry weight of the ⁇ - TCP/collagen biocompatible matrix was used to produce the composition.
- the rhPDGF-BB solution was expelled on the biocompatible matrix with a syringe, and the resulting composition was blended and molded into a thin strand for insertion into a syringe for injection into a site of bone distraction.
- a composition comprising a PDGF solution disposed in a biocompatible matrix was prepared according to the following procedure.
- a dry matrix of soluble bovine collagen weighing about 50 mg was obtained from Kensey Nash of Exton, PA.
- the collagen matrix was added to a 1.5 ml microfuge test tube.
- 1.0 ml of a rhPDGF-BB solution in 20 mM sodium acetate buffer (pH 6.0) was added to the test tube containing the collagen matrix.
- the concentration of the rhPDGF-BB buffer solution was 0.3 mg/ml rhPDGF-BB.
- any desired concentration of rhPDGF-BB can be used.
- the collagen matrix soaked in the rhPDGF-BB buffer solution for about 10 minutes. After 10 minutes, the collagen matrix was removed from the test tube, inverted, and replaced in the test tube to assist in the hydration procedure. The collagen matrix was left in the test tube containing the rhPDGF-BB solution for an additional five minutes.
- the hydrated collagen matrix and any remaining rhPDGF-BB solution in the test tube were placed in a sterile Petri dish.
- the hydrated collagen matrix and any remaining rhPDGF-BB solution was mixed with a sterile spatula to complete the hydration procedure.
- the hydrated collagen matrix was disposed in a first 3 ml syringe. Once in the first syringe, the hydrated collagen matrix was extruded into a second 3 ml syringe. The hydrated collagen matrix was subsequently extruded back into the first 3 ml syringe.
- the back and forth extrusion of the hydrated collagen matrix between the first and second syringes was performed 3 times to convert the hydrated collagen matrix into a flowable putty. Extrusion between the first and second syringes occurred through the open bores of the syringes with no needles attached.
- a 16 gauge needle was added to the 3 ml syringe containing the hydrated collagen matrix, and the hydrated collagen matrix was extruded through the 16 gauge needle.
- the hydrated collagen matrix was subsequently extruded through a 20 gauge needle and loaded in to a 1 ml syringe for disposition at a site of bone distraction.
- 83 male Sprague Dawley rats (age about 6 months old, weight 400-500 g) were randomly divided into five treatment groups as provided in Table 1. Each rat underwent a unilateral mid-diaphyseal femoral lengthening (See Moore et al. J. Orthop. Res. 2003, 21:489- 496). A custom, distractable four-pin monolateral fixator was applied to the right femur, followed by a periosteal-sparing mid-diaphyseal corticotomy to allow femoral lengthening. The wounds were closed in layers and the animals were returned to their cages and allowed unrestricted weight bearing. Following a seven day latency period, the femurs were lengthened 0.17 mm two times per day for 21 days, for a total lengthening of 7 mm.
- rhPDGF-BB solution or buffer was mixed with injectable, soluble bovine collagen in the concentrations delineated in Table 1.
- the soluble bovine collagen was obtained from Kensey Nash of Exton, PA and combined with the PDGF solution or sodium acetate buffer according to the procedure in Example 2.
- BV bone volume fraction in the callus
- BV/TV bone volume fraction in the callus
- FIG. 1 and 2 illustrate BV and BY/TV values for Groups 1-5 at each sacrifice time point. New bone formation was lowest in control Groups 1 and 2, which were not significantly different from one another at any time point.
- BV in Group 3 (0.1 mg/ml rhPDGF-BB) was greater than that in control Groups 1 and 2 on day 56 (p ⁇ 0.05), and BV in Group 5 (1.0 mg/ml rhPDGF-BB) was greater than that in control Groups 1 and 2 on days 42 and 49 (p ⁇ 0.05 for both).
- compositions comprising rhPDGF-BB significantly increases new bone formation during the distraction procedure and accelerates bone union.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Transplantation (AREA)
- Physical Education & Sports Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Inorganic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2693408P | 2008-02-07 | 2008-02-07 | |
PCT/US2009/033596 WO2009100454A1 (en) | 2008-02-07 | 2009-02-09 | Compositions and methods for distraction osteogenesis |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2259807A1 true EP2259807A1 (en) | 2010-12-15 |
EP2259807B1 EP2259807B1 (en) | 2013-04-24 |
Family
ID=40717173
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP09708984.1A Not-in-force EP2259807B1 (en) | 2008-02-07 | 2009-02-09 | Compositions for distraction osteogenesis |
Country Status (10)
Country | Link |
---|---|
US (2) | US7943573B2 (en) |
EP (1) | EP2259807B1 (en) |
JP (3) | JP5864106B2 (en) |
CN (2) | CN102014977B (en) |
AU (1) | AU2009212151C1 (en) |
CA (1) | CA2715254A1 (en) |
ES (1) | ES2422259T3 (en) |
HK (1) | HK1150983A1 (en) |
RU (1) | RU2010137106A (en) |
WO (1) | WO2009100454A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10071182B2 (en) | 2014-10-14 | 2018-09-11 | Samuel E. Lynch | Methods for treating wounds |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7473678B2 (en) * | 2004-10-14 | 2009-01-06 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods of use thereof |
BRPI0618794A2 (en) | 2005-11-17 | 2011-09-13 | Biomimetic Therapeutics Inc | use of a biocompatible matrix, kit and composition for bone augmentation, especially for maxillofacial bone augmentation |
ES2427993T3 (en) | 2006-02-09 | 2013-11-05 | Biomimetic Therapeutics, Llc | Compositions and methods for bone treatment |
US9161967B2 (en) | 2006-06-30 | 2015-10-20 | Biomimetic Therapeutics, Llc | Compositions and methods for treating the vertebral column |
AU2007333425B2 (en) | 2006-11-03 | 2014-03-27 | Biomimetic Therapeutics, Llc | Compositions and methods for arthrodetic procedures |
AU2008218763B2 (en) * | 2007-02-20 | 2013-10-24 | Biomimetic Therapeutics, Llc. | Prevention and treatment for osteonecrosis and osteoradionecrosis of the jaw using PDGF and a bone matrix |
RU2010137106A (en) | 2008-02-07 | 2012-03-20 | Байомайметик Терапьютикс, Инк. (Us) | COMPOSITIONS AND METHODS FOR DISTRACTION OF OSTEOGENESIS |
US9259320B2 (en) | 2008-08-26 | 2016-02-16 | Andy Boiangiu | Apparatus and method for bone augmentation |
US9861482B2 (en) | 2008-08-26 | 2018-01-09 | Andy Boiangiu | Dental bone implant and implant method |
JP6116484B2 (en) * | 2010-12-13 | 2017-04-19 | バイオミメティック セラピューティクス,リミテッド ライアビリティ カンパニー | Compositions and methods for spinal fusion |
RU2665962C1 (en) * | 2017-03-17 | 2018-09-05 | Общество с ограниченной ответственностью "Матрифлекс" | Bioresorable biological matrix for substitution of bone tissue defects and method of its obtaining |
Family Cites Families (210)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3943072A (en) * | 1971-12-15 | 1976-03-09 | United Kingdom Atomic Energy Authority | Separation of molecules |
USRE33161E (en) * | 1982-04-29 | 1990-02-06 | American Dental Association Health Foundation | Combinations of sparingly soluble calcium phosphates in slurries and pastes as mineralizers and cements |
US4654314A (en) | 1983-07-09 | 1987-03-31 | Sumitomo Cement Co., Ltd. | Porous ceramic material and processes for preparing same |
US5187263A (en) * | 1984-10-12 | 1993-02-16 | Zymogenetics, Inc. | Expression of biologically active PDGE analogs in eucaryotic cells |
US4889919A (en) * | 1986-08-13 | 1989-12-26 | Zymogenetics, Inc. | Biologically active PDGF derived A-chain homodimers |
US4766073A (en) * | 1985-02-25 | 1988-08-23 | Zymogenetics Inc. | Expression of biologically active PDGF analogs in eucaryotic cells |
US5165938A (en) | 1984-11-29 | 1992-11-24 | Regents Of The University Of Minnesota | Wound healing agents derived from platelets |
US5629191A (en) | 1985-01-03 | 1997-05-13 | Integra Lifesciences Corporation | Method of making a porous matrix particle |
US5516896A (en) * | 1985-02-25 | 1996-05-14 | Zymogenetics, Inc. | Biologically active B-chain homodimers |
US5045633A (en) | 1985-02-25 | 1991-09-03 | Zymogenetics, Inc. | Expression of biologically active PDGF analogs in eucaryotic cells |
CA1260391A (en) | 1985-03-28 | 1989-09-26 | Karl A. Piez | Xenogeneic collagen/mineral preparations in bone repair |
ZA874681B (en) | 1986-07-01 | 1988-04-27 | Genetics Inst | Novel osteoinductive factors |
US5187076A (en) * | 1986-07-01 | 1993-02-16 | Genetics Institute, Inc. | DNA sequences encoding BMP-6 proteins |
US5108922A (en) | 1986-07-01 | 1992-04-28 | Genetics Institute, Inc. | DNA sequences encoding BMP-1 products |
US5106748A (en) * | 1986-07-01 | 1992-04-21 | Genetics Institute, Inc. | Dna sequences encoding 5 proteins |
US5013649A (en) * | 1986-07-01 | 1991-05-07 | Genetics Institute, Inc. | DNA sequences encoding osteoinductive products |
CA1322714C (en) | 1986-11-14 | 1993-10-05 | Harry N. Antoniades | Wound healing and bone regeneration |
ATE88899T1 (en) | 1986-11-14 | 1993-05-15 | Inst Molecular Biology Inc | WOUND HEALING AND BONE REGENERATION. |
US5019559A (en) * | 1986-11-14 | 1991-05-28 | President And Fellows Of Harvard College | Wound healing using PDGF and IGF-II |
US5124316A (en) * | 1986-11-14 | 1992-06-23 | President And Fellows Of Harvard College | Method for periodontal regeneration |
US5219759A (en) * | 1987-04-22 | 1993-06-15 | Chiron Corporation | Recombinant DNA encoding PDGF A-chain polypeptide and expression vectors |
US5457093A (en) | 1987-09-18 | 1995-10-10 | Ethicon, Inc. | Gel formulations containing growth factors |
US4874746A (en) | 1987-12-22 | 1989-10-17 | Institute Of Molecular Biology, Inc. | Wound headling composition of TGF-alpha and PDGF |
US5759815A (en) * | 1988-02-11 | 1998-06-02 | Creative Biomolecules, Inc. | Production of platelet derived growth factor (PDGF) an muteins thereof |
US6586388B2 (en) | 1988-04-08 | 2003-07-01 | Stryker Corporation | Method of using recombinant osteogenic protein to repair bone or cartilage defects |
US4975526A (en) | 1989-02-23 | 1990-12-04 | Creative Biomolecules, Inc. | Bone collagen matrix for zenogenic implants |
US5129905A (en) * | 1988-04-20 | 1992-07-14 | Norian Corporation | Methods for in situ prepared calcium phosphate minerals |
US5962028A (en) | 1988-04-20 | 1999-10-05 | Norian Corporation | Carbonated hydroxyapatite compositions and uses |
US5053212A (en) | 1988-04-20 | 1991-10-01 | Norian Corporation | Intimate mixture of calcium and phosphate sources as precursor to hydroxyapatite |
US4904259A (en) * | 1988-04-29 | 1990-02-27 | Samuel Itay | Compositions and methods for repair of cartilage and bone |
US5219576A (en) | 1988-06-30 | 1993-06-15 | Collagen Corporation | Collagen wound healing matrices and process for their production |
US5034375A (en) * | 1988-08-10 | 1991-07-23 | Institute Of Molecular Biology, Inc. | Process of wound healing using PDGF and EGF |
US5035887A (en) * | 1989-09-07 | 1991-07-30 | Institute Of Moelcular Biology, Inc. | Wound healing composition of IL-1 and PDGF or IGF-1 |
US5599558A (en) | 1989-09-15 | 1997-02-04 | Curative Technologies, Inc. | Selecting amounts of platelet releasate for efficacious treatment of tissue |
US5112354A (en) * | 1989-11-16 | 1992-05-12 | Northwestern University | Bone allograft material and method |
US5011910A (en) * | 1989-12-28 | 1991-04-30 | Washington University | Reagent and method for determining activity of retroviral protease |
JP3159216B2 (en) | 1990-02-01 | 2001-04-23 | ユニバーシティ オブ サウス フロリダ | Leukocyte-derived growth factor |
TW199858B (en) * | 1990-03-30 | 1993-02-11 | Fujirebio Kk | |
WO1991015231A1 (en) | 1990-04-10 | 1991-10-17 | Institute Of Molecular Biology, Inc. | Wound healing |
US5853746A (en) | 1991-01-31 | 1998-12-29 | Robert Francis Shaw | Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone using functional barrier |
US5149691A (en) | 1991-03-12 | 1992-09-22 | Creative Biomolecules, Inc. | Issue repair and regeneration through the use of platelet derived growth factor (pdgf) in combination with dexamethasone |
US5837258A (en) | 1991-08-30 | 1998-11-17 | University Of South Florida | Induction of tissue, bone or cartilage formation using connective tissue growth factor |
US5270300A (en) | 1991-09-06 | 1993-12-14 | Robert Francis Shaw | Methods and compositions for the treatment and repair of defects or lesions in cartilage or bone |
JP2524858Y2 (en) * | 1991-10-01 | 1997-02-05 | 矢崎総業株式会社 | Screw type connector |
EP0691849B1 (en) * | 1993-03-29 | 1999-06-02 | ZymoGenetics, Inc. | Oesteoblast growth stimulating compostion containing pdgf and vitamin d |
JP2562112B2 (en) * | 1993-07-07 | 1996-12-11 | 三ツ星ベルト株式会社 | V-ribbed belt and grinder wheel for V-ribbed belt |
US5531794A (en) * | 1993-09-13 | 1996-07-02 | Asahi Kogaku Kogyo Kabushiki Kaisha | Ceramic device providing an environment for the promotion and formation of new bone |
US5518680A (en) * | 1993-10-18 | 1996-05-21 | Massachusetts Institute Of Technology | Tissue regeneration matrices by solid free form fabrication techniques |
JP3362267B2 (en) | 1993-12-29 | 2003-01-07 | 日本特殊陶業株式会社 | Bioimplant material and method for producing the same |
US5460962A (en) | 1994-01-04 | 1995-10-24 | Organogenesis Inc. | Peracetic acid sterilization of collagen or collagenous tissue |
US5942496A (en) | 1994-02-18 | 1999-08-24 | The Regent Of The University Of Michigan | Methods and compositions for multiple gene transfer into bone cells |
US7963997B2 (en) * | 2002-07-19 | 2011-06-21 | Kensey Nash Corporation | Device for regeneration of articular cartilage and other tissue |
US6180606B1 (en) * | 1994-09-28 | 2001-01-30 | Gensci Orthobiologics, Inc. | Compositions with enhanced osteogenic potential, methods for making the same and uses thereof |
US5651766A (en) | 1995-06-07 | 1997-07-29 | Transfusion Technologies Corporation | Blood collection and separation system |
US5614206A (en) | 1995-03-07 | 1997-03-25 | Wright Medical Technology, Inc. | Controlled dissolution pellet containing calcium sulfate |
US5635372A (en) | 1995-05-18 | 1997-06-03 | Genetics Institute, Inc. | BMP-15 compositions |
US6287341B1 (en) | 1995-05-19 | 2001-09-11 | Etex Corporation | Orthopedic and dental ceramic implants |
US6027742A (en) | 1995-05-19 | 2000-02-22 | Etex Corporation | Bioresorbable ceramic composites |
US6541037B1 (en) * | 1995-05-19 | 2003-04-01 | Etex Corporation | Delivery vehicle |
US5676976A (en) * | 1995-05-19 | 1997-10-14 | Etex Corporation | Synthesis of reactive amorphous calcium phosphates |
ES2293137T3 (en) * | 1995-10-11 | 2008-03-16 | Novartis Vaccines And Diagnostics, Inc. | COMBINATION OF PDGF, KGF, IGF AND IGFBP FOR WOUND HEALING. |
US5783217A (en) | 1995-11-07 | 1998-07-21 | Etex Corporation | Low temperature calcium phosphate apatite and a method of its manufacture |
US5747273A (en) | 1996-05-07 | 1998-05-05 | Diagnostic Systems Laboratories, Inc. | Immunoassay of total insulin-like growth factor binding protein-1 |
WO1997045147A1 (en) * | 1996-05-28 | 1997-12-04 | 1218122 Ontario Inc. | Resorbable implant biomaterial made of condensed calcium phosphate particles |
FR2749756B1 (en) * | 1996-06-14 | 1998-09-11 | Bioland | PROCESS FOR THE PREPARATION OF AN IMPLANTABLE COMPOSITE MATERIAL, MATERIAL OBTAINED, IMPLANT COMPRISING SUCH MATERIAL, AND IMPLEMENTATION KIT |
US5965403A (en) | 1996-09-18 | 1999-10-12 | Genetics Institute, Inc. | Nucleic acids encoding bone morphogenic protein-16 (BMP-16) |
WO1998016209A2 (en) | 1996-10-16 | 1998-04-23 | Etex Corporation | Bioceramic compositions |
US6037519A (en) * | 1997-10-20 | 2000-03-14 | Sdgi Holdings, Inc. | Ceramic fusion implants and compositions |
DE19646782C2 (en) | 1996-11-13 | 2000-05-25 | Merck Patent Gmbh | Bioresorbable polymerization products from radiation-curable binder systems |
WO1998025963A1 (en) | 1996-12-13 | 1998-06-18 | Chiron Corporation | Analysis and separation of platelet-derived growth factor proteins |
US5866165A (en) | 1997-01-15 | 1999-02-02 | Orquest, Inc. | Collagen-polysaccharide matrix for bone and cartilage repair |
FR2758988B1 (en) | 1997-02-05 | 2000-01-21 | S H Ind | PROCESS FOR THE PREPARATION OF SYNTHETIC BONE SUBSTITUTES OF PERFECTLY MASTERED POROUS ARCHITECTURE |
ATE239514T1 (en) | 1997-02-07 | 2003-05-15 | Stryker Corp | MATRIXLESS OSTEOGENIC DEVICES AND IMPLANTS AND METHOD OF USE THEREOF |
EP0914072B1 (en) | 1997-03-04 | 2004-05-19 | Technology Finance Corporation (Proprietary) Limited | An artefact suitable for use as a bone implant |
US20020098222A1 (en) | 1997-03-13 | 2002-07-25 | John F. Wironen | Bone paste |
US7041641B2 (en) | 1997-03-20 | 2006-05-09 | Stryker Corporation | Osteogenic devices and methods of use thereof for repair of endochondral bone and osteochondral defects |
US20010016646A1 (en) | 1998-03-20 | 2001-08-23 | David C. Rueger | Osteogenic devices and methods of use thereof for repair of endochondral bone, osteochondral and chondral defects |
JP3334558B2 (en) * | 1997-04-23 | 2002-10-15 | 富士レビオ株式会社 | Enzyme immunoassay and test strips |
GB2325934A (en) | 1997-06-03 | 1998-12-09 | Polybiomed Ltd | Treating metal surfaces to enhance bio-compatibility and/or physical characteristics |
US6063624A (en) | 1997-06-09 | 2000-05-16 | Baxter International Inc. | Platelet suspensions and methods for resuspending platelets |
ATE220564T1 (en) | 1997-08-14 | 2002-08-15 | Sulzer Innotec Ag | COMPOSITION AND DEVICE FOR REPAIRING CARTILAGE TISSUE IN VIVO CONSISTING OF NANOCAPSULES WITH OSTEOINDUCTIVE AND/OR CHONDROINDUCTIVE FACTORS |
US6136029A (en) | 1997-10-01 | 2000-10-24 | Phillips-Origen Ceramic Technology, Llc | Bone substitute materials |
US6090998A (en) | 1997-10-27 | 2000-07-18 | University Of Florida | Segmentally demineralized bone implant |
US20020018796A1 (en) * | 1998-01-28 | 2002-02-14 | John F. Wironen | Thermally sterilized bone paste |
DK1100488T3 (en) | 1998-07-28 | 2003-08-11 | Synthes Ag | Use of creatine compounds for the treatment of bone or cartilage cells and tissues |
US20030114936A1 (en) * | 1998-10-12 | 2003-06-19 | Therics, Inc. | Complex three-dimensional composite scaffold resistant to delimination |
US6224635B1 (en) * | 1998-11-06 | 2001-05-01 | Hospital For Joint Diseases | Implantation of surgical implants with calcium sulfate |
US6663870B2 (en) * | 1998-12-07 | 2003-12-16 | Zymogenetics, Inc. | Methods for promoting growth of bone using zvegf3 |
US6231528B1 (en) | 1999-01-15 | 2001-05-15 | Jonathan J. Kaufman | Ultrasonic and growth factor bone-therapy: apparatus and method |
EP1025871A1 (en) | 1999-01-28 | 2000-08-09 | F. Hoffmann-La Roche Ag | Use of a melanoma inhibiting activity factor (MIA) for cartilage and bone repair |
JP2002536077A (en) * | 1999-02-04 | 2002-10-29 | エスディージーアイ・ホールディングス・インコーポレーテッド | Highly mineralized osteogenic sponge compositions and their use |
US6294187B1 (en) | 1999-02-23 | 2001-09-25 | Osteotech, Inc. | Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same |
JP2003026673A (en) * | 1999-03-05 | 2003-01-29 | Asahi Kasei Corp | Osteoplasty accelerator |
BR0005368A (en) | 1999-03-15 | 2001-01-09 | Implant Innovations Inc | Platelet collection system |
US6296602B1 (en) * | 1999-03-17 | 2001-10-02 | Transfusion Technologies Corporation | Method for collecting platelets and other blood components from whole blood |
US6541022B1 (en) * | 1999-03-19 | 2003-04-01 | The Regents Of The University Of Michigan | Mineral and cellular patterning on biomaterial surfaces |
CA2334887C (en) * | 1999-04-12 | 2012-01-24 | Harvest Technologies Corporation | Method and apparatus for producing platelet rich plasma and/or platelet concentrate |
SE515227C2 (en) * | 1999-04-28 | 2001-07-02 | Bruce Medical Ab | Body for providing and growing bone and / or connective tissue and methods for making the body |
US6468543B1 (en) * | 1999-05-03 | 2002-10-22 | Zymogenetics, Inc. | Methods for promoting growth of bone using ZVEGF4 |
US6710025B1 (en) * | 1999-05-26 | 2004-03-23 | The Brigham And Women's Hospital, Inc. | Treatment of damaged tissue using agents that modulate the activity of alpha-smooth muscle actin |
AU5444800A (en) | 1999-05-27 | 2000-12-18 | Research Foundation Of State University Of New York, The | LTiGTin vitroLT/iGT cell culture device including cartilage and methods of usingthe same |
DE19926083A1 (en) | 1999-06-08 | 2000-12-14 | Universitaetsklinikum Freiburg | Biological joint construct |
US6429013B1 (en) | 1999-08-19 | 2002-08-06 | Artecel Science, Inc. | Use of adipose tissue-derived stromal cells for chondrocyte differentiation and cartilage repair |
DE19940717A1 (en) * | 1999-08-26 | 2001-03-01 | Gerontocare Gmbh | Resorbable bone replacement and bone augmentation material |
US6280191B1 (en) * | 1999-09-03 | 2001-08-28 | Christopher B. Gordon | Distractor suitable for permanent implantation into bone |
US6451059B1 (en) | 1999-11-12 | 2002-09-17 | Ethicon, Inc. | Viscous suspension spinning process for producing resorbable ceramic fibers and scaffolds |
US20030199615A1 (en) | 1999-12-09 | 2003-10-23 | Cyril Chaput | Mineral-polymer hybrid composition |
US6479418B2 (en) * | 1999-12-16 | 2002-11-12 | Isotis N.V. | Porous ceramic body |
US20030103960A1 (en) | 1999-12-22 | 2003-06-05 | Pierre Philippart | Sealant and bone generating product |
AU2607701A (en) | 1999-12-29 | 2001-07-09 | Regeneration Technologies, Inc. | System for reconstituting pastes and methods of using same |
PT1250163E (en) | 2000-01-28 | 2005-04-29 | Dot Gmbh | INORGANIC REABSORVIVEL OSSEO REPLACEMENT MATERIAL AND PRODUCTION METHOD |
WO2001057083A1 (en) * | 2000-02-04 | 2001-08-09 | Zymogenetics, Inc. | Methods for promoting growth of bone, ligament, and cartilage using zvegf4 |
EP1286707A2 (en) | 2000-02-18 | 2003-03-05 | Regeneration Technologies, Inc. | Implantable tissues infused with growth factors and other additives |
IT1316769B1 (en) * | 2000-02-18 | 2003-05-12 | Getters Spa | EVACUATED PANEL FOR THERMAL INSULATION WITH REDUCED HEAT CONDUCTING AT THE EDGES |
US7022506B2 (en) * | 2000-02-23 | 2006-04-04 | The Trustees Of The University Of Pennsylvania | Method and device for treating osteoarthritis, cartilage disease, defects and injuries in the human knee |
US20030055511A1 (en) * | 2000-03-03 | 2003-03-20 | Schryver Jeffrey E. | Shaped particle comprised of bone material and method of making the particle |
EP1265637A2 (en) | 2000-03-14 | 2002-12-18 | The University Of Western Ontario | Compositions and methods for affecting osteogenesis |
US20020006437A1 (en) * | 2000-05-01 | 2002-01-17 | Grooms Jamie M. | Non-migration tissue capsule |
US20020022885A1 (en) * | 2000-05-19 | 2002-02-21 | Takahiro Ochi | Biomaterial |
EP1287506A2 (en) | 2000-05-19 | 2003-03-05 | Europrint Holdings Limited | Method and system for implementing a game |
US20020082220A1 (en) * | 2000-06-29 | 2002-06-27 | Hoemann Caroline D. | Composition and method for the repair and regeneration of cartilage and other tissues |
DK177997B1 (en) * | 2000-07-19 | 2015-02-23 | Ed Geistlich Söhne Ag Für Chemische Ind | Bone material and collagen combination for healing of damaged joints |
US6739112B1 (en) * | 2000-08-21 | 2004-05-25 | Nu Vasive, Inc. | Bone allograft packaging system |
GB0020610D0 (en) | 2000-08-21 | 2000-10-11 | Dytech Corp Ltd | Uses of porous carriers |
US6773723B1 (en) | 2000-08-30 | 2004-08-10 | Depuy Acromed, Inc. | Collagen/polysaccharide bilayer matrix |
US20020127265A1 (en) | 2000-12-21 | 2002-09-12 | Bowman Steven M. | Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration |
CA2365376C (en) * | 2000-12-21 | 2006-03-28 | Ethicon, Inc. | Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration |
US7192604B2 (en) * | 2000-12-22 | 2007-03-20 | Ethicon, Inc. | Implantable biodegradable devices for musculoskeletal repair or regeneration |
CA2436162A1 (en) | 2001-01-25 | 2002-08-01 | John F. Wironen | Injectable porous bone graft materials |
US7005135B2 (en) * | 2001-01-30 | 2006-02-28 | Ethicon Inc. | Glass scaffolds with controlled resorption rates and methods for making same |
US6743232B2 (en) * | 2001-02-26 | 2004-06-01 | David W. Overaker | Tissue scaffold anchor for cartilage repair |
US6575986B2 (en) | 2001-02-26 | 2003-06-10 | Ethicon, Inc. | Scaffold fixation device for use in articular cartilage repair |
US6949251B2 (en) * | 2001-03-02 | 2005-09-27 | Stryker Corporation | Porous β-tricalcium phosphate granules for regeneration of bone tissue |
US20030049328A1 (en) * | 2001-03-02 | 2003-03-13 | Dalal Paresh S. | Porous beta-tricalcium phosphate granules and methods for producing same |
US20030109537A1 (en) * | 2001-07-09 | 2003-06-12 | Turner Russell T. | Methods and materials for treating bone conditions |
ATE359836T1 (en) | 2001-09-24 | 2007-05-15 | Millenium Biologix Inc | POROUS CERAMIC COMPOSITE BONE IMPLANTS |
ATE384783T1 (en) * | 2001-10-19 | 2008-02-15 | Zymogenetics Inc | DIMERIZED GROWTH FACTOR AND MATERIALS AND METHODS FOR PRODUCING IT |
US6649072B2 (en) | 2001-11-16 | 2003-11-18 | Robert Brandt | Method for producing autologous platelet-rich plasma |
AU2002361860A1 (en) * | 2001-12-21 | 2003-07-15 | Richard J. Lagow | Calcium phosphate bone replacement materials and methods of use thereof |
EP1499267A4 (en) * | 2002-02-05 | 2008-10-29 | Depuy Mitek Inc | Bioresorbable osteoconductive compositions for bone regeneration |
JP2005523001A (en) | 2002-02-11 | 2005-08-04 | ザイモジェネティクス,インコーポレイティド | Materials and methods for preparing dimeric growth factors |
US7879107B2 (en) * | 2002-02-20 | 2011-02-01 | The Cleveland Clinic Foundation | Composition and method for inducing bone growth and healing |
JP3739715B2 (en) | 2002-03-19 | 2006-01-25 | オリンパス株式会社 | Artificial bone and tissue engineering carrier |
KR100460685B1 (en) | 2002-04-10 | 2004-12-09 | 재단법인서울대학교산학협력재단 | Artificial Bone by Calcium Phosphate Compounds And Method Thereof |
AU2003228587A1 (en) | 2002-04-18 | 2003-11-03 | University Of Florida | Biomimetic organic/inorganic composites, processes for their production, and methods of use |
WO2003105752A2 (en) * | 2002-05-02 | 2003-12-24 | Osteoscreen, Inc. | Methods and compositions for stimulating bone growth using nitric oxide releasing bisphosphonate conjugates (no-bisphosphonate) |
US20040033949A1 (en) * | 2002-05-06 | 2004-02-19 | Genentech, Inc. | Use of VEGF for treating bone defects |
US7368125B2 (en) | 2002-06-05 | 2008-05-06 | Ethicon, Inc. | Amphiphilic polymers for medical applications |
US7041309B2 (en) | 2002-06-13 | 2006-05-09 | Neuropro Technologies, Inc. | Spinal fusion using an HMG-CoA reductase inhibitor |
CA2432583A1 (en) | 2002-06-20 | 2003-12-20 | Merck Patent Gesellschaft Mit Beschraenkter Haftung | Method of preparing alpha- and beta-tricalcium phosphate powders |
US20040002770A1 (en) * | 2002-06-28 | 2004-01-01 | King Richard S. | Polymer-bioceramic composite for orthopaedic applications and method of manufacture thereof |
ATE295744T1 (en) * | 2002-07-11 | 2005-06-15 | Biomet Deutschland Gmbh | METHOD FOR PRODUCING POROUS CALCIUM PHOSPHATE CHIPS AND GRANULES FROM GELATIN PROCESSING |
US7744651B2 (en) * | 2002-09-18 | 2010-06-29 | Warsaw Orthopedic, Inc | Compositions and methods for treating intervertebral discs with collagen-based materials |
WO2004028578A1 (en) * | 2002-09-30 | 2004-04-08 | Regen Biotech, Inc. | Composition for stimulating bone-formation and bone consolidation |
EP1563846B1 (en) | 2002-10-10 | 2012-08-29 | Ono Pharmaceutical Co., Ltd. | Endogenous repair factor production promoters |
US7824701B2 (en) * | 2002-10-18 | 2010-11-02 | Ethicon, Inc. | Biocompatible scaffold for ligament or tendon repair |
US20040078090A1 (en) | 2002-10-18 | 2004-04-22 | Francois Binette | Biocompatible scaffolds with tissue fragments |
JP2006513760A (en) | 2003-02-13 | 2006-04-27 | ジンテーズ アクチエンゲゼルシャフト クール | Injectable bone replacement compound |
AU2004212942A1 (en) | 2003-02-14 | 2004-09-02 | Depuy Spine, Inc. | In-situ formed intervertebral fusion device |
WO2004078069A2 (en) | 2003-03-05 | 2004-09-16 | Therics, Inc. | Process for manufacturing biomedical articles by infiltrating biocompatible metal alloys in porous matrices |
US20040193270A1 (en) | 2003-03-31 | 2004-09-30 | Depuyacromed, Inc. | Implantable bone graft |
US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
WO2004110308A2 (en) | 2003-06-11 | 2004-12-23 | Osteotech, Inc. | Osteoimplants and methods for their manufacture |
US6974862B2 (en) | 2003-06-20 | 2005-12-13 | Kensey Nash Corporation | High density fibrous polymers suitable for implant |
EP1491164B1 (en) | 2003-06-24 | 2008-05-28 | Dr. h. c. Robert Mathys Foundation | Prosthetic device for cartilage repair |
DE10328892A1 (en) | 2003-06-26 | 2005-05-12 | Curasan Ag | Bone building agent and manufacturing process |
JP5148873B2 (en) | 2003-06-27 | 2013-02-20 | エチコン、インコーポレイテッド | Umbilical tissue-derived postpartum cells and methods for making and using the same |
FI20031120A0 (en) | 2003-07-31 | 2003-07-31 | Bci Bioabsorbable Concepts Ltd | Multifunctional implant device |
US7163920B2 (en) | 2003-09-30 | 2007-01-16 | Ethicon, Inc. | Peptide with osteogenic activity |
CU23352A1 (en) * | 2003-10-16 | 2009-03-16 | Centro Nacional De Investigaciones Cientificas | COMPOSITE BIOMATERIALS FOR BONE IMPLANTS |
ES2522575T3 (en) | 2003-10-22 | 2014-11-17 | Encelle, Inc. | Bioactive hydrogel compositions for connective tissue regeneration |
US20050098915A1 (en) * | 2003-11-07 | 2005-05-12 | Smith & Nephew Inc. | Manufacture of bone graft substitutes |
US7215995B2 (en) | 2003-11-14 | 2007-05-08 | The Trustees Of The University Of Pennsylvania | Method and device for treating osteoarthritis and cartilage disease, defects, and injuries in the human hip |
DE10355559A1 (en) | 2003-11-21 | 2005-06-23 | Orthogen Ag | Transskin |
EP1537839A1 (en) | 2003-12-02 | 2005-06-08 | Dr. h. c. Robert Mathys Foundation | Prosthetic device for cartilage repair |
NZ579516A (en) | 2004-01-27 | 2011-01-28 | Osteotech Inc | Stabilized bone graft |
US7189263B2 (en) * | 2004-02-03 | 2007-03-13 | Vita Special Purpose Corporation | Biocompatible bone graft material |
US11395865B2 (en) | 2004-02-09 | 2022-07-26 | DePuy Synthes Products, Inc. | Scaffolds with viable tissue |
US7671012B2 (en) | 2004-02-10 | 2010-03-02 | Biosurface Engineering Technologies, Inc. | Formulations and methods for delivery of growth factor analogs |
US7928059B2 (en) | 2004-02-24 | 2011-04-19 | Wisconsin Alumni Research Foundation | Use of neuropeptides for traumatic cartilage injury |
KR101013999B1 (en) | 2004-03-19 | 2011-02-14 | 재단법인서울대학교산학협력재단 | Membrane and implant immobilized osteogenic enhancing peptides on the surface |
US20070190101A1 (en) | 2004-03-31 | 2007-08-16 | Chunlin Yang | Flowable bone grafts |
WO2006031388A2 (en) | 2004-08-20 | 2006-03-23 | Hyperbranch Medical Technology, Inc. | Dentritic polymers, crosslinked gels, and their uses in orthopedic applications |
EP1804716A2 (en) | 2004-09-21 | 2007-07-11 | The Massachusetts Institute Of Technology | Gradient scaffolding and methods of producing the same |
US7473678B2 (en) * | 2004-10-14 | 2009-01-06 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods of use thereof |
US7250550B2 (en) | 2004-10-22 | 2007-07-31 | Wright Medical Technology, Inc. | Synthetic bone substitute material |
JP2006122518A (en) * | 2004-10-29 | 2006-05-18 | Univ Nagoya | Composition for forming bone or periodontium |
WO2006050493A2 (en) | 2004-11-03 | 2006-05-11 | The Regents Of The University Of Michigan | Biodegradable implant for intertransverse process fusion |
WO2007008250A2 (en) | 2004-12-07 | 2007-01-18 | Gelwell Biotech Corporation | Biomaterials for guided tissue regeneration and target drug delivery |
US20060151383A1 (en) | 2005-01-12 | 2006-07-13 | Aaf-Mcquay Inc. | Pleated corrugated media and method of making |
US7621963B2 (en) | 2005-04-13 | 2009-11-24 | Ebi, Llc | Composite bone graft material |
ES2516690T5 (en) | 2005-06-07 | 2017-11-21 | The Regents Of The University Of Colorado, A Body Corporate | Serine protease activity inhibitors and their use in methods and compositions for the treatment of graft rejection and graft survival promotion |
BRPI0618794A2 (en) * | 2005-11-17 | 2011-09-13 | Biomimetic Therapeutics Inc | use of a biocompatible matrix, kit and composition for bone augmentation, especially for maxillofacial bone augmentation |
US7749555B2 (en) | 2006-01-25 | 2010-07-06 | Medtronic, Inc | Modification of chemical forces of bone constructs |
EP1974015A4 (en) | 2006-01-27 | 2012-07-04 | Univ California | Biomimetic scaffolds |
US20070178159A1 (en) | 2006-01-30 | 2007-08-02 | Alza Corporation | In-Situ Forming Porous Scaffold |
ES2427993T3 (en) * | 2006-02-09 | 2013-11-05 | Biomimetic Therapeutics, Llc | Compositions and methods for bone treatment |
US7833270B2 (en) | 2006-05-05 | 2010-11-16 | Warsaw Orthopedic, Inc | Implant depots to deliver growth factors to treat osteoporotic bone |
WO2007133451A1 (en) | 2006-05-08 | 2007-11-22 | Nuvasive, Inc. | Cancellous bone treated with collegenase and essentially free of blood cells |
WO2008005427A2 (en) * | 2006-06-30 | 2008-01-10 | Biomimetic Therapeutics, Inc. | Pdgf-biomatrix compositions and methods for treating rotator cuff injuries |
US9161967B2 (en) | 2006-06-30 | 2015-10-20 | Biomimetic Therapeutics, Llc | Compositions and methods for treating the vertebral column |
AU2007333425B2 (en) * | 2006-11-03 | 2014-03-27 | Biomimetic Therapeutics, Llc | Compositions and methods for arthrodetic procedures |
AU2008218763B2 (en) * | 2007-02-20 | 2013-10-24 | Biomimetic Therapeutics, Llc. | Prevention and treatment for osteonecrosis and osteoradionecrosis of the jaw using PDGF and a bone matrix |
CA2689986C (en) | 2007-06-04 | 2020-04-07 | Biomimetic Therapeutics, Inc. | Compositions and methods for treating the vertebral column |
US8357384B2 (en) * | 2007-06-15 | 2013-01-22 | Warsaw Orthopedic, Inc. | Bone matrix compositions and methods |
WO2009042514A1 (en) * | 2007-09-25 | 2009-04-02 | Integra Lifesciences Corporation | Flowable wound matrix and its preparation and use |
RU2010137106A (en) * | 2008-02-07 | 2012-03-20 | Байомайметик Терапьютикс, Инк. (Us) | COMPOSITIONS AND METHODS FOR DISTRACTION OF OSTEOGENESIS |
CA2735885C (en) | 2008-09-09 | 2018-08-28 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries |
MX2011006586A (en) | 2008-12-19 | 2011-06-30 | Biomimetic Therapeutics Inc | Bone grafts with reduced protease activity and methods of selection and use. |
WO2010102266A1 (en) | 2009-03-05 | 2010-09-10 | Biomimetic Therapeutics, Inc. | Platelet-derived growth factor compositions and methods for the treatment of osteochondral defects |
-
2009
- 2009-02-09 RU RU2010137106/15A patent/RU2010137106A/en not_active Application Discontinuation
- 2009-02-09 CA CA2715254A patent/CA2715254A1/en not_active Abandoned
- 2009-02-09 WO PCT/US2009/033596 patent/WO2009100454A1/en active Application Filing
- 2009-02-09 JP JP2010546096A patent/JP5864106B2/en not_active Expired - Fee Related
- 2009-02-09 ES ES09708984T patent/ES2422259T3/en active Active
- 2009-02-09 US US12/368,242 patent/US7943573B2/en active Active
- 2009-02-09 AU AU2009212151A patent/AU2009212151C1/en active Active
- 2009-02-09 CN CN200980113167.6A patent/CN102014977B/en not_active Expired - Fee Related
- 2009-02-09 CN CN201510455152.5A patent/CN105854074B/en not_active Expired - Fee Related
- 2009-02-09 EP EP09708984.1A patent/EP2259807B1/en not_active Not-in-force
-
2011
- 2011-03-15 US US13/048,795 patent/US8349796B2/en active Active
- 2011-05-24 HK HK11105181.5A patent/HK1150983A1/en not_active IP Right Cessation
-
2015
- 2015-07-16 JP JP2015142020A patent/JP6248068B2/en not_active Expired - Fee Related
-
2017
- 2017-06-02 JP JP2017109754A patent/JP2017145261A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO2009100454A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10071182B2 (en) | 2014-10-14 | 2018-09-11 | Samuel E. Lynch | Methods for treating wounds |
Also Published As
Publication number | Publication date |
---|---|
AU2009212151B2 (en) | 2015-05-21 |
CN105854074B (en) | 2019-10-15 |
AU2009212151C1 (en) | 2015-09-17 |
US8349796B2 (en) | 2013-01-08 |
CN102014977B (en) | 2015-09-02 |
HK1150983A1 (en) | 2012-01-20 |
US7943573B2 (en) | 2011-05-17 |
JP6248068B2 (en) | 2017-12-13 |
CN105854074A (en) | 2016-08-17 |
AU2009212151A1 (en) | 2009-08-13 |
JP2011511808A (en) | 2011-04-14 |
US20090232890A1 (en) | 2009-09-17 |
JP2015180705A (en) | 2015-10-15 |
JP5864106B2 (en) | 2016-02-17 |
CA2715254A1 (en) | 2009-08-13 |
RU2010137106A (en) | 2012-03-20 |
ES2422259T3 (en) | 2013-09-10 |
JP2017145261A (en) | 2017-08-24 |
EP2259807B1 (en) | 2013-04-24 |
CN102014977A (en) | 2011-04-13 |
US20110165245A1 (en) | 2011-07-07 |
WO2009100454A1 (en) | 2009-08-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8349796B2 (en) | Methods for treatment of distraction osteogenesis using PDGF | |
EP3181157B1 (en) | Compositions and methods for arthrodetic procedures | |
US20190365946A1 (en) | Compositions and Methods for Spine Fusion Procedures | |
US20100151025A1 (en) | Prevention and treatment for osteonecrosis and osteoradionecrosis of the jaw | |
WO2008151193A1 (en) | Compositions and methods for treating the vertebral column | |
US20200297897A1 (en) | Platelet-Derived Growth Factor Formulations for Enhancing Spine Fusion | |
AU2013203287B2 (en) | Compositions and methods for arthrodetic procedures | |
AU2017213462A1 (en) | Compositions and methods for spine fusion procedures | |
AU2013203292A9 (en) | Compositions and methods for treating the vertebral column |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20100907 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA RS |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: LYNCH, SAMUEL, E. Inventor name: HART, CHARLES, E. Inventor name: EHRLICH, MICHAEL, G. Inventor name: MOORE, DOUGLAS, C. |
|
17Q | First examination report despatched |
Effective date: 20110304 |
|
DAX | Request for extension of the european patent (deleted) | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1150983 Country of ref document: HK |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 608198 Country of ref document: AT Kind code of ref document: T Effective date: 20130515 |
|
RAP2 | Party data changed (patent owner data changed or rights of a patent transferred) |
Owner name: BIOMIMETIC THERAPEUTICS, LLC |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
RAP2 | Party data changed (patent owner data changed or rights of a patent transferred) |
Owner name: BIOMIMETIC THERAPEUTICS, LLC |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602009015201 Country of ref document: DE Effective date: 20130627 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: NV Representative=s name: E. BLUM AND CO. AG PATENT- UND MARKENANWAELTE , CH |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2422259 Country of ref document: ES Kind code of ref document: T3 Effective date: 20130910 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 608198 Country of ref document: AT Kind code of ref document: T Effective date: 20130424 |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: VDEP Effective date: 20130424 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130826 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130824 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: BE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130724 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130725 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130724 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1150983 Country of ref document: HK |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20140127 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602009015201 Country of ref document: DE Effective date: 20140127 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20140209 Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 8 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20090209 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 9 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 10 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20130424 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20211217 Year of fee payment: 14 Ref country code: IE Payment date: 20211209 Year of fee payment: 14 Ref country code: GB Payment date: 20211216 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20211216 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20211214 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20220111 Year of fee payment: 14 Ref country code: ES Payment date: 20220303 Year of fee payment: 14 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R119 Ref document number: 602009015201 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20230209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230228 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230228 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230209 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230209 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230209 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230209 Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230228 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230901 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20240405 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230210 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20230210 |